Annual Review of Immunology

Control of Immunity
by the Microbiota
Eduard Ansaldo,1,∗ Taylor K. Farley,1,2,∗
and Yasmine Belkaid1,3
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1
Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National
Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20814, USA;
email: [email protected]
2
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and
Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom
3
Microbiome Program, National Institute of Allergy and Infectious Diseases, Bethesda,
Maryland 20892, USA

Annu. Rev. Immunol. 2021. 39:449–79 Keywords

The Annual Review of Immunology is online at
microbiota, barrier tissue, immunity, T cell, B cell, antibodies,
immunol.annualreviews.org
unconventional T cell
https://doi.org/10.1146/annurev-immunol-093019-
112348 Abstract
This is a work of the US government and not subject
The immune system has coevolved with extensive microbial communities
to copyright protection in the United States
living on barrier sites that are collectively known as the microbiota. It is in-
∗
These authors contributed equally to this article.
creasingly clear that microbial antigens and metabolites engage in a constant
dialogue with the immune system, leading to microbiota-specific immune
responses that occur in the absence of inflammation. This form of homeo-
static immunity encompasses many arms of immunity, including B cell re-
sponses, innate-like T cells, and conventional T helper and T regulatory re-
sponses. In this review we summarize known examples of innate-like T cell
and adaptive immunity to the microbiota, focusing on fundamental aspects
of commensal immune recognition across different barrier sites. Further-
more, we explore how this cross talk is established during development, em-
phasizing critical temporal windows that establish long-term immune func-
tion. Finally, we highlight how dysregulation of immunity to the microbiota
can lead to inflammation and disease, and we pinpoint outstanding questions
and controversies regarding immune system–microbiota interactions.

449
 1. INTRODUCTION
Multicellular organisms exist as meta-organisms, comprising both the macroscopic host and its
symbiotic microbiota (1). These complex communities of microbes that include bacteria, fungi,
viruses, and other microbial and eukaryotic species play a fundamental role in controlling all as-
pects of host physiology, including the immune system (2).
The immune system is composed of a complex network of innate and adaptive components
endowed with an extraordinary capacity to adapt and respond to highly diverse challenges. Col-
lectively this cellular network acts as a formidable regulator of host homeostasis able to sustain
and restore tissue function in the context of microbial and environmental encounters. The de-
velopment of specific arms of the immune system, and in particular those associated with adap-
tive immunity, coincided with the acquisition of a complex microbiota, supporting the idea that
a large fraction of this complex system evolved to maintain the symbiotic relationship with these
microbes. In turn the microbiota promote and calibrate all aspects of the immune system, ranging
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

from hematopoiesis to the induction of cognate responses. The impact of the microbiota begins
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during development, and early encounters with microbes are believed to set the stage for the im-
mune system for the long term. Sustained calibration of the immune threshold of activation by the
microbiota plays a fundamental role in the promotion of protective immunity against infectious
agents. This adjuvant property has also been proposed to account for the impact of the microbiota
in vaccine responses and cancer immune checkpoint therapy (3, 4).
The vast majority of immune system–microbial encounters and associated immune responses
result from the symbiotic relationship of the host with its microbiota. Far from being ignored, as
originally postulated, microbes at all barrier surfaces promote the induction of immune responses,
including those directed at the microbiota itself. What differentiates these responses from those
resulting from encounters with pathogenic microbes is that both initiation of immune responses
to the microbiota and accumulation of commensal-specific lymphocytes within tissues occur in
the absence of inflammation, a process that has been referred to as homeostatic immunity (5). As
further discussed in this review, homeostatic immunity to the microbiota represents a distinct and
likely dominant class of immune responses able to control numerous aspects of host physiology,
including tissue repair.
Acquisition of a complex immune system and its reliance on the microbiota also came at a
price. Pathologies that increasingly affect humans such as allergies and autoimmune and inflam-
matory disorders all arise from a failure to control misdirected immune responses against self,
environmental antigens, and/or the microbiota (6, 7). Microbiota alteration resulting from an-
tibiotic usage, diet variation, and elimination of constitutive partners such as helminthic worms
is believed to have transformed our microbial allies into potential liabilities. Genetic predisposi-
tion or infection can promote dominance by proinflammatory microbes, expression of virulence
genes, and/or acquisition of new invasive microorganisms. This, in turn, can trigger aberrant im-
mune responses to the microbiota, an inflammatory loop that eventually leads to a breakdown
of tissue homeostasis. However, an important point to consider is how, in most cases, microbe-
induced pathogenicity strongly depends on context. As such traditional reliance on Koch’s pos-
tulates (8) has often proven counterproductive in exploring the impact of the microbiota, and
we should consider microbial causation in a broader systems biology context in which host ge-
netic variability, health status, exposure history, and microbial strains and communities are all
integrated.
In this review, we focus on the known and proposed mechanisms underlying early-life and
long-term imprinting of the immune system by the microbiota, with a particular focus on adaptive
immunity induced by the microbiota and the broad impact of these responses on host homeostasis.

450 Ansaldo • Farley • Belkaid

 2. ESTABLISHMENT OF MICROBIOTA–IMMUNE SYSTEM
HOMEOSTASIS DURING A SPECIFIC DEVELOPMENTAL WINDOW
When operating properly, early host-microbiota interactions lead to the establishment of durable
and mutualistic relationships, a dialog that sets the lifelong host immune threshold. On the other
hand, early-life stressors such as malnutrition, infection, and mode of delivery are emerging as
important factors altering long-term immune function, and human epidemiological studies have
confirmed that this critical time of microbial exposure can have lasting consequences for disease
susceptibility (9, 10). The immune system is uniquely susceptible to long-term programming by
the microbiota and maternal-derived factors in the postnatal period. This form of developmental
plasticity has been hypothesized to provide greater adaptability: Alternative homeostatic set points
of immunity would be programmed in early life based on perinatal exposures in anticipation of
the adult environment for greater adaptability. However in the context of maladapted microbial
encounters, such flexibility could also contribute to increased disease susceptibility (11).
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Birth is a pivotal step in development of the organism. Upon delivery, neonates face tissue-
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specific colonization of barrier sites by microbes derived from the mother and the environment.
During early life, introduction of solid foods and cessation of breastfeeding bring additional chal-
lenges in the form of expansion and restructuring of fluctuating microbial communities (12).
Microbiota–immune system interactions during this critical developmental window are thought
to pave the way for homeostasis and disease susceptibility in the adult, yet the mechanisms that
coordinate these interactions remain poorly understood. Experimental evidence has started to
uncover some of the mechanisms and sequences of events mediating host-commensal mutual-
ism in early life and long-term consequences of these early encounters. Notably, maternal factors
and nutrients present in breast milk shape the microbiota and responses to these microbes. Fur-
ther, temporally regulated processes guide early-life interactions with the microbiota and dictate
homeostatic set points of host immunity. Finally, specific subsets of cells enriched at an early stage,
including innate-like lymphocytes and unconventional T cells as well as regulatory T (Treg) cells,
guide microbiota-immune dialog in early life.
In this section we summarize our understanding of microbial exposures in early life and their
effects on host immunity (Figure 1), and we discuss known and proposed mechanisms of immune
education in early life. This discussion focuses on innate-like and adaptive lymphocyte cross talk
with the microbiota but also briefly discusses additional maternal, fetal, and environmental factors
of early life with the potential to affect immune interactions with the microbiota in the long term.

2.1. Microbial Education Begins In Utero

While the fetal environment has traditionally been considered sterile, with microbial exposure
starting only upon birth, the existence of commensal microbes resembling human oral and skin
microbiota in the placenta and amniotic fluid has been reported (13, 14). However, these findings
have been called into question (15, 16). Regardless of true colonization, in utero influence of
the maternal microbiota on the developing fetus can be mediated directly via microbiota-derived
products or metabolites or indirectly via the ability of the microbiota to control the tone of the
maternal immune system.
The placenta allows for transport of gases and small molecules into the fetus, while it is con-
sidered to be largely impermeable to diffusion of large macromolecules (17). Receptor-mediated
transcytosis via the neonatal Fc receptor (FcRn) allows for the transfer of antibodies into the
fetus (18), but to what extent additional macromolecules use similar transport mechanisms re-
mains poorly understood. Recent animal studies have revealed that maternal microbiota-derived

www.annualreviews.org • Control of Immunity by the Microbiota 451

 Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org
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In utero In utero Neonate Suckling

(human) (mouse) (mouse) (mouse)

Developmental window for Treg and MAIT cells

452
Life-long imprinting of disease susceptibility

Maternal Milk-derived factors Microbiota-derived factors

microbiota

Ansaldo
Maternal Maternal IgG Riboflavin Sphingolipid

•
IgA derivatives
Maternal Maternal Microbial Oligosaccharides

Farley
Maternal Maternal EGF

•
IgG IgG ligands
cytokines? cytokines? Beneficial
Microbiota-derived Immune cell microbes
products? Metabolites

Belkaid
Placenta Commensal
FcRn
T/B cell
TLR5 reactivity
γδ T

γδ T
Regulates
colonization

Treg

Homeostatic
CD4+ γδ T set point
Th
Tolerance
Treg to microbiota
Treg
Cxcl16
Effector
cytokines iNKT iNKT accumulation
Immune development CD71+
B1 in adult
of ILC3s and MNCs CD4+
Th
Commensal T
Peyer’s Commensal myeloid MAIT cell reactivity
patch cell reactivity

(Caption appears on following page)

 Figure 1 (Figure appears on preceding page)
Early-life microbiota–immune system interactions establish homeostatic set points of immunity. Education of the immune system
begins in utero, where immune populations are developing and seeding peripheral tissues, including B1 B cells and γδ T cells in both
mice and humans and CD4+ T effector (Th) and Treg cells in humans. Maternal microbiota-derived metabolites, antibody-bound
microbial ligands, and cytokines can reach the developing fetus and impact immune development. After birth, maternal factors
transmitted through milk, including maternal antibodies, EGF, and milk oligosaccharides, further modulate immune development and
early encounters with the microbiota. Maternal antibodies prevent aberrant T cell reactivity to the microbiota and help establish the
long-term homeostatic set point of Treg cells. Microbiota-derived factors impact the development and long-term function of
unconventional T cells. For example, the microbiota induce hypermethylation upstream of the Cxcl16 locus in epithelial cells,
preventing aberrant iNKT cell accumulation in adulthood. Furthermore, during this window, microbiota-derived sphingolipids inhibit
iNKT cell proliferation, and microbiota-derived riboflavin derivatives promote the development of MAIT cells in the thymus and their
accumulation in peripheral tissues. Developmental programs also impact immune reactivity to the microbiota: CD71+ erythroid cells
inhibit proinflammatory responses to the microbiota, and an increased frequency of Treg cells promotes tolerance to the colonizing
microbiota. Finally, broad expression of TLR5 by epithelial cells in utero is downregulated after birth and confined to Paneth cells in
the adult small intestine, thereby impacting microbiota assembly. Abbreviations: EGF, epidermal growth factor; FcRn, neonatal Fc
receptor; ILC3, group 3 innate lymphoid cell; iNKT, invariant natural killer T; MAIT, mucosal-associated invariant T; MNC,
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

mononuclear cell; Th, T helper; TLR5, Toll-like receptor 5; Treg, regulatory T. Figure adapted from image created with
Access provided by 105.111.250.190 on 02/12/24. For personal use only.

BioRender.com.

metabolites [e.g., short-chain fatty acids (SCFAs)] and ligands are able to reach the fetus and
impact tissue development (19). A reversible colonization model has been used in which germ-free
pregnant dams are colonized with an auxotrophic Escherichia coli strain that does not persist such
that the dams give birth to germ-free pups. This study revealed that microbial metabolites and
antibody-bound microbial fragments derived from the maternal microbiota can reach the fetus
and impact intestinal group 3 innate lymphoid cell (ILC3) and mononuclear cell populations in
the offspring (20) (Figure 1).
The indirect impact of the maternal microbiota on the offspring’s physiology has been pro-
posed to contribute to the etiology of neurodevelopmental disorders (21). For instance, specific
gut commensal bacteria can increase abnormalities consistent with autism spectrum disorder in
the offspring of pregnant mothers undergoing immune system activation (22). In this model ma-
ternal IL-17A promoted abnormal cortical development in the fetus (23), and while transplacental
transport of IL-17A was not conclusively shown, this and previous work suggest that specific ma-
ternal cytokines may be able to reach the fetus and impact its development (23, 24).
The human immune system and tissue architecture reach greater maturity in utero compared
to that of mice (Figure 1): T and B cell development in the mouse fetus encompasses innate-like
B1 B cells and γδ T cells (25, 26), with αβ T cells first appearing around birth and accumulat-
ing in secondary lymphoid structures and peripheral tissues postnatally (27, 28). In human fetal
development, incomplete fetal B cell tolerance leads to the accumulation of polyreactive naive B
cells with commensal specificities (29). Furthermore, mature αβ T cells including memory CD4+
T cells with the capacity for cytokine secretion and evidence of clonal expansion seed peripheral
human tissues in utero (30, 31). The role of this preset and potentially microbiota-reactive T and
B cell repertoire in shaping early life encounters with the microbiota remains to be determined.
For a more comprehensive review on human prenatal immune development see Reference 32.
More generally, researchers are at an early stage of investigating the impact of the microbiota on
both maternal and fetal immune function and the impact of the temporal windows associated with
these defining encounters.

2.2. Maternal Factors Instruct Host-Microbiota Homeostasis in the Offspring

In addition to seeding the primordial microbiota in the infant’s tissues (12, 33, 34), the mother is
also a source of immunomodulatory factors that guide the offspring’s initial response to the mi-
crobiota (Figure 1). These factors include maternal antibodies, transferred in utero and through
www.annualreviews.org • Control of Immunity by the Microbiota 453
 breastfeeding, as well as other components enriched in maternal milk: growth hormones, and
nutrients such as oligosaccharides that are able to promote the expansion of specific constituents
of the microbiota (35).
Maternal antibodies have long been recognized to provide the offspring with passive immunity
against infection (36, 37). Furthermore, maternal antibodies are emerging as a key player in shap-
ing initial interactions with the microbiota. A study in preterm infants revealed that necrotizing
enterocolitis, an inflammatory disease driven by the microbiota, is associated with a decrease in
IgA binding to the microbiota and a bloom of IgA-unbound Enterobacteriaceae, a family of com-
mensals with proinflammatory potential. Mouse models confirmed a protective role for maternal
IgA against necrotizing enterocolitis (38). Furthermore, maternal antibodies, which have broad
commensal-reactive specificities, limit adaptive immune reactivity to the microbiota in early life
(39) and impact microbiota composition into adulthood (40) (Figure 1). In the absence of mater-
nal antibodies, suckling mice have reduced body weight and develop compensatory T-dependent
immune responses in early life (39). Further, the homeostatic set point of colonic RORγt+ Tregs
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is vertically transmitted during a short postnatal window by maternal IgA. RORγt+ Tregs, in turn,
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control intestinal and milk IgA levels, thus transmitting this set point throughout multiple gen-
erations (41). In summary, maternal antibodies orchestrate early interactions with the microbiota,
although the mechanisms remain incompletely understood.
Additional maternal factors present in breast milk also control initial interactions with the
offspring’s microbiota. Epidermal growth factor (EGF) is highly abundant in breast milk at birth
and coordinates commensal antigen uptake and induction of commensal T cell reactivity in the gut
through modulation of goblet-associated passages (42). Furthermore, milk-derived EGF controls
the timing of a programmed inflammatory reaction to the microbiota around the time of weaning
(42, 43). How alterations in reactivity to the microbiota during this window stably imprint disease
susceptibility remains to be addressed, but these studies may identify mechanisms that explain
epidemiological observations revealing that perinatal exposures have long-term impacts on disease
susceptibility (9).
Milk is also rich in maternal leukocytes with an activated phenotype that express gut- and
lung-homing receptors (44). While the functional relevance of maternal milk–derived leukocytes
in the offspring in early life remains unclear, evidence supports the idea that specific subsets in-
cluding CD8+ T cells transiently engraft in offspring Peyer’s patches and present an activated
phenotype in mice (45). Milk is also the earliest substrate upon which the neonatal microbiota
grow. In turn, it has profound impacts on microbial composition and downstream immunological
effects. Milk is rich in oligosaccharides, specifically sialylated oligosaccharides, which act as pre-
biotics for beneficial microbes, many belonging to the phylum Actinobacteria (35). Bifidobacterium
species in particular play many beneficial roles for the developing offspring, including improved
responses to vaccines (46, 47), enhanced epithelial barrier function (48), and protection from en-
teropathogenic infection (49). Additionally, in studies of breast milk from mothers with healthy or
severely stunted offspring, sialylated oligosaccharides were sufficient to induce beneficial, long-
term metabolic shifts in gnotobiotic animals by modulating the gene expression profiles of some
microbiota members (35).

2.3. Early-Life Developmental Programs Guide Initial Interactions

with the Microbiome
At birth, the neonate is tasked with the formidable challenge to interact with microbiota acquired
via both the mother and the environment and to develop mutualistic interactions with micro-
bial communities at all barrier sites. In physiological settings, these phenomena can in part be

454 Ansaldo • Farley • Belkaid

 explained by the relative immaturity of the neonatal immune system at birth and the regulatory
environment that defines early mammalian life (30) (Figure 1). For instance, CD71+ erythroid
cells, which contribute to immune cell–extrinsic immunosuppression during this period through
arginine depletion, can blunt inflammatory responses of myeloid cells to the intestinal microbiota
(50). In contrast to adult T cells, neonatal T cells are poised for rapid differentiation with a bias
toward becoming FOXP3-expressing Treg or Th2 cells (51). Furthermore, the frequency of Treg
cells in secondary lymphoid organs and mucosal tissues is greater during early life than in adult-
hood (52, 53).
Experimental studies have revealed that early life presents a unique window for the generation
of Treg responses to the microbiota: In mouse skin, Treg cells abruptly accumulate in neonatal
skin by day 13, and Treg cell responses to Staphylococcus epidermidis, a skin commensal, are prefer-
entially induced during this early period (54). Impaired Treg cell responses to S. epidermidis during
neonatal exposure lead to increased inflammation upon secondary exposure to this commensal in
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the context of barrier disruption (54). Early life also presents a unique window for antigen sam-
pling and Treg cell responses to the microbiota in the intestine (42), and a transient defect in Treg
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cells during this period leads to susceptibility to inflammatory pathology later in life (42, 43).
Within the lung, early-life exposure to the microbiota promotes local accumulation of Treg cells,
a phenomenon that limits susceptibility to allergic airway inflammation (55). Importantly, ablating
early-life Treg cell responses does not alter total adult Treg frequencies in the tissue in any of these
models, as Treg cells can still occupy their niche in adulthood (42, 43). However, disease suscep-
tibility is sustained, suggesting that antigen specificity, functional capacity of neonatal Treg cells
induced by the microbiota, or both are critical to maintain tissue homeostasis later in life. Sim-
ilarly, B1 B cell repertoire specificities are uniquely programmed during early life. For instance,
the repertoire of antibody responses to Streptococcus pyogenes induced by neonatal colonization is
distinct from responses to the same microbe seen later in life (56).
Taken together, these studies show that during the neonatal period multiple and still poorly
understood developmental programs are deployed to establish homeostatic responses to the mi-
crobiota. These early responses are now believed to set up the host immune threshold for the
long term. As the study of early-life immunity progresses, additional temporally regulated, tissue-
specific mechanisms coordinating interactions with the microbiota remain to be uncovered.

2.4. Unconventional T Cells and Early-Life Responses to the Microbiota

A growing body of evidence supports a role for innate-like/unconventional T cells, an evolutionar-
ily ancient arm of the immune system, in the control of early-life interactions with the microbiota
(Figure 1). In contrast to conventional T cells, which have the potential to recognize an almost
limitless diversity of peptides, unconventional T cells recognize a set of conserved antigens, such
as modified peptides and small molecules including lipids and other metabolites (57). A large frac-
tion of unconventional T cells are restricted by monomorphic major histocompatibility class Ib
(MHC-Ib) molecules, and many express semi-invariant T cell receptors (TCRs), including invari-
ant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells (57,
58). As such, unconventional T cell recognition of microbial ligands can be considered as bridg-
ing germ line–encoded innate immune receptors and randomly generated adaptive TCRs and
B cell receptors. These cell subsets typically acquire the capacity for cytokine release and tissue
tropism during development, prior to thymic egress, and accumulate in tissues prior to the arrival
of conventional effector cells (26, 59). The ability of MHC-Ib molecules to present antigens with
specific chemical or amino acid sequence motifs, which can be derived from a large constituency
of the microbiota, places unconventional T cells as ideal candidates for the constitutive sensing

www.annualreviews.org • Control of Immunity by the Microbiota 455

 and recognition of microbiota-derived antigens and metabolites. For example, MAIT cells rec-
ognize riboflavin derivatives from microbiota metabolism that are presented on MR1 (60), and
iNKT cells can respond to microbe-derived lipid antigens bound by CD1d (61). As such, uncon-
ventional T cells may be optimally positioned to control early-life communication between the
microbiota and the immune system.
Adequate seeding of tissues with unconventional T cells depends on exposure to specific mi-
crobes during key developmental windows. For example, iNKT cell accumulation in mucosal
tissues is regulated by the microbiota in the postnatal period. Increased CXCL16 expression in
the colon and lungs of adult germ-free mice leads to aberrant accumulation of iNKT cells and
greater susceptibility to asthma and colitis (62). These effects can only be rescued by neonatal
exposure to the microbiota. Furthermore, neonatal but not adult exposure to sphingolipids pro-
duced by Bacteroides fragilis can prevent aberrant iNKT cell accumulation in the colon by locally
inhibiting iNKT cell proliferation (63) (Figure 1). The development of MAIT cells is also de-
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

pendent on early-life exposure to microbes that produce riboflavin derivatives during an early-life
window (64), and impaired microbiota-derived antigen exposure in early life leads to irreversible
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defects in MAIT cells (64–66). Microbes belonging to the order Enterobacterales, Proteus mirabilis
and Klebsiella oxytoca, were sufficient for MAIT cell development, and perhaps uncoincidentally,
members of this order are highly enriched in the neonatal gut and decrease in abundance with age
(67). Taken together, these studies argue that the microbiota establish homeostatic set points of
nonconventional T cell populations in early life. These fundamental interactions between uncon-
ventional T cells and early-life microbiota also support the idea that innate-like immune responses
may have been sustained throughout evolution as a means to promote early responses to the mi-
crobiota prior to the establishment of adaptive immune responses.

3. IMMUNE RECOGNITION OF THE MICROBIOTA

As mentioned above, the vast majority of microbial encounters and associated immune responses
result from the symbiotic relationship of the host with its microbiota. Notably, the microbiota
express an extraordinary number of putative antigens for both conventional and unconventional
lymphocytes (Table 1). As such, the vast majority of antigens seen by the immune system both in
the context of homeostasis and during inflammatory states are expected to be microbiota derived.
The corollary of this is that the vast majority of effector and memory B and T cells may be mi-
crobiota specific. A remarkable property of these responses is that, in contrast to those induced by
infections, initiation of T and B cell responses to the microbiota and accumulation of these cells
in tissues occur in the absence of inflammation, a process referred to as homeostatic immunity.
Emerging evidence supports the idea that a major aspect of the microbiota’s effect on the im-
mune system, including the induction of cognate noninflammatory responses to the microbiota,
is reinforcement of barrier function and integrity so as to constrain the microbiota’s ecological
niche. Homeostatic immunity to the microbiota is a distinct and likely dominant class of immune
responses, regulated by specific processes and able to control numerous aspects of host physiol-
ogy. In this section, we review our understanding of immune recognition of the microbiota by
innate-like T cells and adaptive lymphocytes, focusing on the ontogeny, specificity, and function
of commensal-specific responses at barrier sites (for recent reviews on innate immunity and the
microbiota, see References 68 and 69).

3.1. Humoral Immunity to the Microbiota

Antibodies play a major role not only in the establishment of early-life dialog with the microbiota
but also in the maintenance of life-long interaction with microbial partners via impacts on

456 Ansaldo • Farley • Belkaid

 Table 1 Examples of defined interactions between the immune system and members of the microbiota
Dominant immune Downstream
Microbe Microbial product Known antigens impact consequences References

Humoral responses
Enterobacteriaceae spp. NA NA IgG Protection against 101
related pathogens
Akkermansia muciniphila NA NA Cognate Tfh cell 90
T-dependent IgG1
and IgA
Mucispirillum spp. NA NA T-dependent IgA 88
SFB NA NA T-dependent IgA 88

Unconventional T cell responses

Staphylococcus epidermidis NA N-Formylated peptides Tc17 cell Wound healing 119–121
(fMIIINA)
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Numerous microbes, e.g., NA Riboflavin derivatives MAIT cell Wound healing 64

Proteus mirabilis, (5-OP-RU)
Klebsiella oxytoca,
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Staphylococcus epidermidis
Corynebacterium spp. Mycolic acid NA IL-17-producing Protective immu- 126, 127
γδ T cell nity/inflammation

T cell responses
SFB NA QFSGAVPNKTD Antigen-specific Th17 Protective immunity 88, 132–138
cell Enhanced systemic
Th17 responses
Clostridium spp. NA Flagellin Antigen-specific IgA Immunoregulation 42
(DMATEMVKY- and Treg cell
SNANILSQAGQ) (homeostasis)
Th1 or Th17 cell 110
(inflammation)
Numerous microbes, e.g., Short-chain fatty NA Treg cell Immunoregulation 187, 188
Clostridium spp. acids
Helicobacter hepaticus NA GNAYISVLAHYGKNG Antigen-specific Treg Immunoregulatory 158
and Tfh cell response to
(homeostasis) Helicobacter
hepaticus
Antigen-specific Th17 158–162
and Th1 cell
(inflammation)
Akkermansia muciniphila NA TLYIGSGAILS Antigen-specific Tfh, 90
LIFESSNALGLGR Th1, Th2, Treg,
and Th17 cell
(context dependent)
Bacteroides fragilis Capsular factor NA Treg cell Suppression of 194, 195
polysaccharide A inflammation
Bifidobacterium bifidum Surface NA Treg cell 193
B-glucan/galactan
Staphylococcus epidermidis NA NA Tc17 and Th17 cell Protective 119, 120
(homeostasis) immunity/wound
healing
Th17 cell with poised Th2 cytokine- 121
Th2 transcriptome mediated
inflammation
Treg cell (early life) Immunoregulatory 54
response to
Staphylococcus
epidermidis

Abbreviations: MAIT, mucosal-associated invariant T; NA, not applicable (microbial products or known antigens have not yet been described); SFB, seg-
mented filamentous bacteria; Tc17, H2-M3-restricted CD8+ T; Tfh, T follicular helper; Th17, T helper 17; Treg, regulatory T.

www.annualreviews.org • Control of Immunity by the Microbiota 457

 microbial localization and function. While IgAs have long been recognized for this fundamen-
tal role, more recent work revealed that other isotypes, including IgGs, are also involved in
microbiota-immune cross talk (Figure 2).
IgA antibodies represent a key aspect of immunity at mucosal barriers. The J chain polypeptide
mediates the dimerization of IgA and pentamerization of IgM, enabling their secretion into the
lumen through polymeric immunoglobulin receptors. Here, secretory IgA and IgM (SIgA and
SIgM) provide protection against toxins and invading pathogens but also control host-commensal
interactions by controlling microbiota composition, localization, and function (70) and limiting
aberrant adhesion to epithelial surfaces (71) (Figure 2). As further discussed below, some of these
IgAs can express broad reactivity toward diverse members of the microbiota, supporting the idea
that together with unconventional T cells, IgAs may contribute to a canonical form of immunity
to overcome the extraordinary antigenic diversity contained within the microbiota.
IgA accounts for a dominant fraction of antibody production, with intestinal IgA+ plasma cells
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(PCs) constituting 80% of all PCs in humans (72). Part of the intestinal microbiota is coated
with IgA antibodies (73, 74), and observations of germ-free mice revealed that intestinal IgA+
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PCs are largely dependent on microbial colonization (75). Early seminal studies uncovered a T
cell-independent arm of the IgA response to commensal bacteria (76) and revealed that lack of
activation-induced cytidine deaminase (AID)-dependent antibodies leads to aberrant expansion
of anaerobic bacteria and isolated lymphoid follicle (ILF) hyperplasia (77). Since then, much work
has been devoted to characterizing the ontogeny, specificity, and function of microbiota-reactive
antibodies (also reviewed in References 57 and 58) (Figure 2).
Mucosal IgA responses to the microbiota are thought to be induced locally by B1 and B2 pre-
cursors, via both T-independent (TI) and T-dependent (TD) pathways (78–81). However, the ex-
act contribution of each of these pathways in the control of host-microbiota interactions remains
an object of active investigation. TI, in situ class-switch recombination (CSR) to IgA can occur
in the lamina propria and ILFs and involves interactions with the epithelial cell– or dendritic
cell–derived ligands BAFF and APRIL (79, 82, 83). Additional factors present in the intestinal
microenvironment, such as retinoic acid and TGF-β, have also been implicated in gut homing
and IgA CSR (80, 84, 85). Furthermore, intestinal epithelial cell endoplasmic reticulum stress
induces the activation and proliferation of peritoneal B1 cells and recruitment of microbiota-
reactive, TI PCs to the intestine (86). TD IgA responses in Peyer’s patches, including those of
microbiota-reactive IgA, require B cell CD40-CD40L interactions with T cells, which lead to
upregulation of CCR6 in B cells, subsequent migration to the subepithelial dome by the acti-
vated B cell, and local dendritic cell–mediated activation of TGF-β and IgA class-switching (80)
(Figure 2).
Sequencing of members of the microbiota bound to IgA has enabled the exploration of the
landscape of IgA responses to commensal bacteria. This revealed that IgA predominantly targets
bacteria that reside in the small intestine (87, 88). T cells appear to be dispensable for most com-
mensal IgA binding, while select taxa such as segmented filamentous bacteria (SFB) and Mucispir-
illum spp. require TD responses for IgA coating (88) (Figure 2). Indeed, a large fraction of IgA
antibodies have natural polyreactive specificities and bind multiple structurally diverse antigens
and commensal bacteria with low affinity (81). Furthermore, the presence of somatic hypermuta-
tion (SHM) in some of these sequences does not confer increased affinity, arguing that TD affinity
maturation may not play a major role in some microbiota-reactive IgA (81, 89). However, TD ex-
amples of high-affinity antibody responses to commensal microbiota do occur (87, 90, 91), and
the extent to which TI and TD responses contribute to commensal-specific IgA is still debated
(87, 89). Regardless, in the absence of T cells, the levels of intestinal IgA PCs and luminal IgA are
severely reduced (76, 88), supporting the idea that T cells do play important roles in enabling IgA

458 Ansaldo • Farley • Belkaid

 Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org
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Function
Specificity
Local responses Limiting motility Modulation of
T-dependent IgA: gene expression
high specificity Immune exclusion
and affinity

T-independent IgA:
broad, polyreactive
specificities Antigen sampling

Mucispirillum spp.
DC

SFB Niche Enchained

occupancy growth

PC
Akkermansia
muciniphila
Ontogeny

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PC

•
IgM+ DC
B2

Tfh TGF-β
Systemic responses
Peyer’s
T-dependent patch
CD40/40L
IgG1 IgM+ IgA+
Highly selective B2 B2
BAFF APRIL
T-independent Systemic responses
IgG2b/IgG3 ? IgA+
Broad reactivity B1
T-dependent:
IgG1 IgM+ DC
B1

Control of Immunity by the Microbiota

? IgM+ Isolated
T-independent: Epithelial ER lymphoid
IgG2b/IgG3 IgM+ B1
B1 stress? follicle

459
Peritoneum

(Caption appears on following page)

 Figure 2 (Figure appears on preceding page)
Commensal-reactive T-dependent and T-independent antibody responses control host-microbiota mutualism. Specificity:
T-dependent and -independent IgAs coat a large and diverse fraction of the microbiota at homeostasis. Systemic, T-independent IgG2b
and IgG3 responses also target a diverse and overlapping fraction of commensal bacteria, whereas IgG1 and IgA responses that are
highly selective to immunostimulatory members of the microbiota are induced in a T-dependent manner. Ontogeny: B1 cells are a
major contributor to T-independent IgA, and potentially to IgG2b and IgG3. B1 cells are thought to migrate from the peritoneum to
the intestine in response to poorly characterized signals, including intestinal epithelial ER stress, and undergo class-switch
recombination in response to local factors including epithelial- and dendritic cell–derived BAFF and APRIL. T-dependent IgA
responses occur locally in lymphoid structures such as the Peyer’s patches from naive B2 cells. Interactions with antigen-specific Tfh
cells induce migration of B cells to the subepithelial dome, where interactions with dendritic cells induce TGF-β-mediated class-switch
recombination to IgA. The ontogeny of systemic IgG1 and IgG2b/3 remains unclear but is thought to originate from similar B cell
precursors as IgA responses. Function: Limiting bacterial motility, enabling occupancy of mucosal-associated niches, preventing
antigen uptake and immune activation, enchainment of growing bacteria limiting invasion, and modulation of bacterial gene expression
have all been proposed as functions of microbiota-reactive antibodies. Abbreviations: DC, dendritic cell; ER, endoplasmic reticulum;
PC, plasma cell; Tfh, T follicular helper. Figure adapted from image created with BioRender.com.
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

responses to the microbiota. Furthermore, mice carrying a mutation in AID that abrogates SHM
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but allows CSR revealed that SHM, not just IgA class-switching, is required to prevent aberrant
expansion of small-intestine microbiota and germinal center hyperplasia (92). Finally, abundant
IgA coating in the context of inflammatory bowel disease identifies specific members of the mi-
crobiota with the potential to drive intestinal inflammation (91), and IgA binding also identifies
microbial taxa capable of inducing enteropathy in undernourished children (93). Previous work
supported the idea that mucosal IgA responses may lack classical memory characteristics and are
able to change according to fluctuations in microbiota composition. Indeed, established mucosal
IgA specificities are outcompeted by novel antibacterial responses allowing the mucosal immune
system to respond to a constantly changing microbiota (94, 95). Whether this phenomenon is
true for TI and TD responses remains to be addressed. Thus, the current model is that IgA re-
sponses to the microbiota include both TI and TD specificities that play complementary roles in
the control of host-microbiota responses.
Selective IgA deficiency is the most common primary immunodeficiency in humans (96). How-
ever, a large percentage of individuals are asymptomatic, and compensatory mechanisms such as
increased secretory IgM have been reported (96). Indeed, IgM and IgG antibodies also play im-
portant roles in protection of many barrier sites (97), and while IgM+ and IgG+ PCs are mostly
absent from the murine intestine, they are abundant in the human gut (89, 98, 99). This observa-
tion may reflect the fact that mice are raised in pathogen-free settings and in the absence of natu-
ral stressors. Early seminal work suggested that IgG antibodies do not recognize most commensal
bacteria during homeostasis and that commensal IgG recognition is predominantly induced in
the context of intestinal barrier breach (100). Indeed, invasive members of the Enterobacteriaceae
family that are able to reach systemic sites induce IgG antibodies that can protect against related
pathogens (101). However, during homeostasis, mice mount systemic IgG antibody responses to
a large, phylogenetically diverse fraction of the intestinal microbiota (39). The bulk of this re-
sponse consists of TI, Toll-like receptor (TLR)-dependent IgG2b and IgG3 antibodies, and the
large overlap between IgG2b/3- and IgA-targeted commensals suggests that they may share sim-
ilar specificities and ontogeny (39). Additionally, a small subset of commensal bacteria, including
Akkermansia muciniphila, are targeted by high-affinity TD IgG1 and induce cognate T follicular
helper (Tfh) responses (90). Thus, similarly to the case of IgA, both TI and TD IgG responses to
the microbiota are induced and target different subsets of commensal bacteria (Figure 2).
Recent efforts have been devoted to elucidating the role of antibodies, and in particular IgA,
in the control of host-microbiota mutualism. Study of the divergent adaptive immune system
of teleosts revealed that their secretory immunoglobulin (SIgT) is involved in both protection

460 Ansaldo • Farley • Belkaid

 from mucosal infections and establishment of homeostasis with the microbiota (102); similar ob-
servations have been made of other adaptive immune systems. Like SIgA in mammals, SIgT in
rainbow trout coats a significant fraction of the microbiota during homeostasis, and IgT depletion
leads to marked dysbiosis, loss of SIgT-targeted taxa, microbial translocation, and tissue damage
(102). Consequently, this study argues that mediating mutualistic interactions with the micro-
biota is an ancestral function of secretory antibodies arising early in the evolution of the adaptive
immune system. A plethora of functions have been suggested for microbiota-reactive IgA an-
tibodies (Figure 2). Attributing differences in microbiota composition to a specific factor such
as IgA requires rigorous experimental design to avoid caveats with microbiome variability and
drift (103). Still, many studies argue that IgA antibodies regulate the colonization, diversity, and
composition of bacterial communities in the intestine (40, 104, 105). A variety of mechanisms
have been invoked (Figure 2). For example, IgA can enable colonization of a privileged mucus-
associated niche for some commensal species (106), and enchainment of dividing bacteria may
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

limit invasiveness (107). Furthermore, TLR5-dependent, flagellin-binding IgA can limit bacterial
motility and overall flagellin expression by the microbiota (108). Additionally, use of a Bacteroides
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thetaiotaomicron monocolonization system in Rag1−/− mice carrying a hybridoma that produced

B. thetaiotaomicron–specific IgA suggested both direct and indirect in vivo modulation of bacterial
gene expression by IgA (70). Microbiota-specific IgA can mediate immune exclusion of its targets,
retaining antigen in the intestinal lumen and preventing further priming of immune responses:
Flagellin-specific, TD IgA prevents systemic activation of CBir1 TCR transgenic T cells, which
are specific for a commensal flagellin (109). This observation, coupled with programmed early-life
antigen uptake of CBir1 flagellin (42), may help explain why CBir1 flagellin-specific T cells re-
main naive during homeostasis and are only activated during a specific early-life window (42) or in
the context of barrier breach (110). Conversely, polyreactive IgA antibodies may instead enhance
bacterial delivery to the Peyer’s patches in the small intestine (105), which could increase immune
priming. Finally, commensal-reactive antibodies can also positively and negatively impact disease
outcomes: Systemic IgA, which unlike mucosal IgA is mostly TD, can protect against sepsis af-
ter barrier breach and bacteremia (111). On the other hand, microbiota-specific IgG antibodies,
which are increased in ulcerative colitis patients, can contribute to pathogenesis by activating in-
testinal macrophages through Fc receptors and fueling inflammation (112). While most of what
we understand today about the role of antibodies in host-microbiota interactions derives from the
exploration of the gut environment, it is known that in humans, IgA is secreted at other mucosal
surfaces as well as within the skin surface by eccrine and sebaceous glands (113). The impact of
these responses on microbiota composition and function remains to be addressed.
In conclusion, the evolution of antibodies is tightly linked to their role in maintaining homeo-
static relationships with the microbiota. In mammals, TD and TI commensal-reactive specificities
have unique ontogenies and appear to target functionally distinct subsets of commensal bacteria
while exhibiting a range of potential homeostatic functions. However, we have yet to address how
distinct subsets or pathways contribute to the control of host-microbiota homeostasis at distinct
developmental stages or in specific contexts.

3.2. Unconventional Immunity to the Microbiota

In addition to their role in early life, unconventional and innate-like lymphocytes contribute to the
long-term maintenance of homeostatic responses to the microbiota. Indeed, as discussed above,
in Section 2.4, the ability of unconventional T cells to respond to canonical antigens derived from
a large fraction of the microbiota makes these cells powerful regulators of tissue physiology, with
an increasingly appreciated role in tissue repair (Figure 3).

www.annualreviews.org • Control of Immunity by the Microbiota 461

 Microbiota-derived factors
Lipid Riboflavin fMet Mycolic acid
antigens derivatives peptides

Homeostasis

Staphylococcus
epidermidis Microbiota
Invasive
microbes
Fungal Corynebacterium spp.
infection

MyD88
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γδ IEL REGIIIγ
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Microbiota

IL-17 γδ IEL
AMP H2-M3
Tight-junction Tc17
formation
IL-17 ?
Lysozyme

IL-17 MAIT IL-23

Paneth
cell
MAIT
iNKT IL-17 γδ+

Injury/inflammation

Alarmins
γδ IEL
Microbiota IL-13 H2-M3
Tc17

Tissue repair

Epithelial γδ IEL MAIT

regeneration

KGF

(Caption appears on following page)

462 Ansaldo • Farley • Belkaid

 Figure 3 (Figure appears on preceding page)
Unconventional T cells engage in a lifelong dialog with the microbiota and control tissue homeostasis.
Unconventional T cells, including γδ T cells, MAIT cells, iNKT cells, and Tc17 cells, seed barrier tissues
such as the skin and gut, where they control numerous physiological tissue responses. These include
regulation of the microbiota composition and promotion of tissue repair. In response to epithelial MyD88
signaling, gut epithelium–resident γδ T cells produce the AMP REGIIIγ, which in turn regulates microbial
composition and localization. Colonization can also be regulated indirectly in response to microbial
antigens: Microbiota-derived lipids induce iNKT-dependent Paneth cell secretion of lysozyme. Within the
skin, IL-17-producing H2-M3-restricted CD8+ T cells accumulate in the epidermis in response to
Staphylococcus epidermidis–derived N-formylated peptides. These T cells promote the production of AMPs in
an IL-17A-dependent manner, thereby enhancing protection against subsequent infection. MAIT cells and
γδ T cells are also enriched within the skin and respond to microbiota-derived metabolites, microbiota-
induced cytokines, or both. In the gut, γδ T cell–derived IL-17A contributes to tight-junction formation
between enterocytes, and following tissue injury these cells are potent producers of the epithelial mitogen
KGF. Skin-resident unconventional T cells, including MAIT cells and H2-M3-restricted CD8+ T cells, also
contribute to wound healing in an IL-13-dependent manner. Abbreviations: AMP, antimicrobial peptide;
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

fMet, N-formylated; IEL, intraepithelial lymphocyte; iNKT, invariant natural killer T; KGF, keratinocyte
growth factor; MAIT, mucosal-associated invariant T; Tc17, H2-M3-restricted CD8+ T. Figure adapted
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from image created with BioRender.com.

Throughout life, barrier tissues are marred by frequent inflammatory insults requiring rapid
induction of repair mechanisms that are under the control of several redundant cell subsets and
pathways. One of the first indications of a role for the microbiota in tissue repair was the obser-
vation that, in the gut, TLR activation by commensals is required to protect the host from acute
injury (114). Dendritic epidermal T cells were the first subset of unconventional T cells linked to
tissue repair, a property that has since been attributed to numerous other subsets of innate-like or
nonclassically restricted T cells (115). Within the gut, intraepithelial γδ T cells are the majority of
innate-like T cells within the epithelium and contribute to mucosal repair via the production of
keratinocyte growth factor (KGF) (116) (Figure 3). MAIT cells from both humans and mice con-
stitutively express a wound healing program (64, 117). Within the skin, MAIT cells can make up a
significant portion of lymphocytes: up to 40% of the αβ T cells in mice and approximately 2% of
CD3+ lymphocytes in humans (64, 118). The enrichment within this tissue could be explained by
the fact that a significant portion of the skin microbiota express the machinery associated with the
production of MAIT cell antigens (64). Following skin colonization with S. epidermidis, a commen-
sal capable of synthesizing riboflavin derivatives, MAIT cells significantly expand and contribute
to wound repair (64) (Figure 3). Similarly, S. epidermidis promotes the induction of nonclassical
MHC-Ib-restricted CD8+ T cells (119–121). Topical exposure to a particular clade of S. epider-
midis also promotes the induction and tissue accumulation of H2-M3-restricted CD8+ T cells
specific for commensal-derived N-formyl-containing peptides (120). Within the epidermis these
commensal-specific IL-17-producing CD8+ T cells can promote tissue repair by releasing IL-13
in response to tissue alarmins (119–121) (Figure 3). While H2-M3 is absent in humans (58), we
could postulate that alternate mechanisms of antigen presentation may be in place to recognize
these highly abundant microbiota-derived N-formylated peptides.
Unconventional T cells also regulate microbiota composition and protect against microbial
invasion. For instance, γδ T cells from the intraepithelial lymphocyte (IEL) compartment pro-
mote production of the antimicrobial peptide REGIIIγ at steady state and constrain the micro-
biota in the context of mucosal damage (122, 123). The immunomodulatory, antibacterial pro-
gram expressed by γδ T cells is controlled by the microbiota itself, and microbial sensing via
epithelial MyD88 governs γδ T cell metabolism and dynamics of epithelial surveillance (122, 124)
(Figure 3). Responses of iNKT cells to microbe-derived lipid antigens presented by CD1d (58)

www.annualreviews.org • Control of Immunity by the Microbiota 463

 regulate intestinal Paneth cell function and production of lysozyme, an enzyme that catalyzes the
destruction of bacterial cell walls (125). As such, iNKT cells can indirectly limit bacterial transloca-
tion across the intestinal barrier (125) (Figure 3). Further, nonclassical MHC-Ib-restricted CD8+
T cells induced by skin commensals can promote the production of antimicrobial peptides by ker-
atinocytes, thereby promoting heterologous protection against subsequent fungal infection (119)
(Figure 3). Similarly, within the eye, IL-17-producing γδ T cells elicited in response to the com-
mensal microbe Corynebacterium mastitidis provide heterologous protection against ocular fungal
infections via local increase in antimicrobial peptides (126). Within the skin, IL-17-producing
γδ T cells also respond to colonization with Corynebacterium in a mycolic acid/IL-23-dependent
manner (127) (Figure 3). The nature of the antigens recognized by γδT cells remains largely un-
known, but these cells are believed to also recognize lipid and phosphoantigens (128), a point of
particular relevance for potential recognition of commensal-derived products. MAIT cells have
also been proposed to contribute to antimicrobial defense, and a large number of bacteria and
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

yeast, including pathogens, are prolific producers of riboflavin derivatives (60, 129).
Emerging evidence supports the idea that the fundamental role of innate-like T cells may result
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from their action as a network of cells with overlapping and potentially synergistic functions rather
than as individual subsets. For instance, H2-M3-restricted CD8+ T cells, MAIT cells, and γδ T
cells all produce type 17 cytokines involved in barrier function and immune surveillance (64, 119,
126, 127) (Figure 3). These cell subsets also compete for a shared physiological niche (64, 66).
This phenomenon was recently confirmed in a patient harboring a homozygous point mutation
in MR1 associated with the absence of MAIT cells and concomitant expansion of γδ T cells (130).
The redundancy of innate-like T cells and ability to compete for similar survival factors or niches
may have been maintained through evolution as a way to increase tissue resilience and long-term
protection of host homeostasis.

3.3. T Cell Responses to the Microbiota

As discussed above, microbes at all barrier surfaces constitutively engage the immune system and
promote the induction of cognate responses, including noninflammatory responses directed at the
microbiota itself (131). Together with unconventional responses, adaptive T cell responses to the
microbiota converge to broadly and contextually control tissue homeostasis.
While the microbiota as a whole can promote all aspects of host immunity, individual species
or groups of bacteria can be the predominant influence on the immune system under steady state
(Figure 4). SFB are a prototype of such keystone species in the gastrointestinal tract. These spore-
forming, gram-positive anaerobic bacteria colonize the terminal ileum of mice and have a domi-
nant effect on the mucosal immune system by promoting the accumulation of Th17 cells as well
as driving the production of IgA (132–136). Notably, SFB-specific Th17 cells not only promote
local antimicrobial defenses but also impact local and systemic inflammatory responses (133, 136–
138). In contrast to most members of the microbiota that reside outside of the gut demilitarized
zone (139), SFB interact closely with their host via tight adhesion to Peyer’s patches and epithelial
cells (140, 141). Indeed, intimate contact with epithelial cells, a property shared by a minority of
commensal organisms, is proposed to account for the ability of specific microbes to preferentially
induce immune responses and heighten tissue immunity (133, 142).
In vivo screening of phylogenetically distinct bacteria in monocolonized germ-free mice
supports the idea that only a handful of microbes can promote and enhance accumulation of ef-
fector T cells. For example, Coprobacillus induces IL-10-expressing T cells, Bifidobacterium longum
induces Th1 cells, and Bifidobacterium adolescentis promotes Th17 cells (143, 144). However, it is
important to acknowledge that while informative, studies using monocolonized germ-free mice

464 Ansaldo • Farley • Belkaid

 have obvious limitations since physiological responses depend on the preexistence of a complex
microbiota. Studies with defined bacteria consortia in gnotobiotic animals also reveal that the
ability to stimulate effector T cell responses is microbe and consortium dependent (145). Early
studies examining T cell immunity to a clostridial flagellin (CBir1) revealed that CBir1-specific T
cells remain naive during homeostasis in the context of a complex microbiota (109), arguing that
some commensal antigens may indeed be ignored (Figure 4). However, lack of CBir1-specific
T cell activation during homeostasis depends on preexisting antigen-specific IgA (109), and
subsequent studies revealed that CBir1 antigen is sampled and induces antigen-specific Treg cell
responses during an early-life window via temporally regulated goblet-associated passages (42).
This suggests that while continuous antigen sampling and T cell activation may not occur, initial
encounters with this antigen can lead to immune recognition and T cell activation (143, 144).
Whether induction of cognate immunity to all gut commensals is the norm as opposed to being
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

Homeostasis Dysbiosis/immune
Primary dysregulation
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bile acids

Infection or
Microbiota Clostridium spp. barrier breach
Secondary
bile acids

SCFA Helicobacter
hepaticus
Naive Naive
CBir1 CBir1
DC Treg Akkermansia Helicobacter hepaticus
muciniphila SFB
Ignorance?
IL-10 CBir1
RA Teff

TGF-β Tolerance
DC C-MAF SAA 1/2 Inflammation
Naive Treg
Th1
IL-17
IL-10 Th17 Th17
Th17 T-dependent IFN-γ

Tfh IgA Treg Naive

IgG1 Th17 IL-17
Treg Th17
Peyer patch

Homeostasis Inflammation/immune dysregulation

Staphylococcus
Staphylococcus Pathogenic Candida spp. epidermidis
epidermidis microbes

IL-18

AMP
IL-17
MHC-II Il5
Il13
Th17 IL-10 Treg Inflammation Th17 mRNA
Th1 IFN-γ IL-17
Th17
Il5
Il13 Th2 Treg IL-10
Th17
mRNA
Inflammation
(Caption appears on following page)

www.annualreviews.org • Control of Immunity by the Microbiota 465

 Figure 4 (Figure appears on preceding page)
Microbiota-specific T cell immunity in homeostasis and disease. Treg cells are induced in response to
microbiota colonization. Microbiota-derived metabolites, including SCFAs and secondary bile acids, impact
Treg cell development and tissue accumulation via action on Treg cells or via DCs. SFB induce homeostatic
Th17 cells in the small intestine, and SFB adhesion to epithelial cells leads to production of SAA1 and SAA2,
which act on local Th17 cells to license IL-17 production. Akkermansia muciniphila induces a strong Tfh
response in Peyer’s patches in gnotobiotic settings, but in the context of a complex microbiota, A. muciniphila
promotes various cell subsets, including Th17, Th1, and Treg cells. Helicobacter hepaticus induces RORγt+
Treg cells during homeostasis. However, in the context of immune dysregulation, such as in the absence of
IL-10, Helicobacter hepaticus–specific T cells adopt a proinflammatory Th17 program with coexpression of
IL-17 and IFN-γ, leading to tissue inflammation. CBir1-specific T cells remain naive during homeostasis
but adopt proinflammatory fates during infection or intestinal inflammation. Within the skin, Staphylococcus
epidermidis induces classical Th1 and Th17 responses. Th1 cell accumulation within the skin is controlled by
keratinocyte MHC-II expression. Tc17 (Figure 3) and Th17 responses to S. epidermidis enhance protection
from subsequent infections by inducing AMP expression. S. epidermidis–specific Th17 cells also express a
poised type II transcriptome, leading to the production of type 2 cytokines in the context of tissue injury and
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exposure to local alarmins such as IL-18. Type 2 cytokine production by commensal-specific T cells
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promotes tissue repair in an IL-13-dependent manner but can also contribute to tissue inflammation in the
context of defects in local regulation. Preexisting fungus-specific Th17 cells can contribute to inflammation
in the context of psoriasis. Abbreviations: AMP, antimicrobial peptide; DC, dendritic cell; MHC, major
histocompatibility complex; RA, retinoic acid; SAA, serum amyloid A; SCFA, short-chain fatty acid; SFB,
segmented filamentous bacteria; Tc17, H2-M3-restricted CD8+ T; Teff, T effector; Tfh, T follicular helper;
Th, T helper; Treg, regulatory T. Figure adapted from image created with BioRender.com.

restricted to specific microbes remains difficult to confirm at this stage, and further development
of tools allowing us to track commensal-specific T cells in both mice and humans is required to
address this fundamental question.
Most bacteria and commensal fungi colonizing the skin can promote commensal-specific T
cell responses (119, 146, 147) (Figure 4). The ability of the skin to rapidly respond to new mi-
crobes could be, in part, explained by the low density of resident microbes within the skin and their
localization in highly specialized appendages such as hair follicles and sebaceous glands (148). As
discussed in Section 3.2, commensal S. epidermidis–specific T cells (classical and nonclassical) accu-
mulate within the epidermis, where they constitutively act on keratinocytes in an IL-17-dependent
manner to promote antimicrobial peptide production and enhanced responses against subsequent
infections (119). This ability of commensal-specific T cells to broadly heighten tissue immunity
and promote heterologous immunity is conserved across barrier tissues (133).
The microbiota play a dominant role in the control of tissue repair via numerous mecha-
nisms, including promotion of T cell responses that remodel or repair tissue (64, 120, 121, 149,
150). Commensal-specific T cells promote immunity and tissue repair through distinct molecular
mechanisms. Indeed, within the skin, commensal-specific, RORγt-expressing CD4+ and CD8+
T cells (but not those induced by infection) coexpress a poised type 2 transcriptome that can be
unleashed in the context of tissue injury and exposure to alarmins such as IL-18 (121). As such,
upon tissue damage, release of type 2 cytokines and in particular IL-13 by commensal-specific T
cells directly contributes to their ability to promote tissue repair (121). Thus, commensal-specific
T cells can co-opt tissue residency and cell-intrinsic flexibility as a means to promote both local
immunity and tissue adaptation to injury.
Tissues not only dictate the induction of responses directed toward the microbiota but also
provide specific checkpoints allowing the functional licensing of commensal-specific T cells
(Figure 4). Indeed, upon accumulation in tissues, commensal-specific T cells exert their lo-
cal function via the release of cytokines such as IL-17A and IL-22, the production of which is
tightly regulated by tissue-specific cues. For instance, within the skin, local production of IL-1α is

466 Ansaldo • Farley • Belkaid

 required to license cutaneous T cells to release IL-17A (151), while the vast majority of Th17 re-
sponses to the gut microbiota can develop in the absence of this cytokine (140). On the other hand,
within the gut, serum amyloid A (SAA) proteins play a central role in the control of homeostatic
Th17 responses. Notably, colonization of mice with microbes able to adhere to the epithelium,
such as SFB, triggers the local secretion of SAA1 and SAA2 by epithelial cells that remain con-
fined to the ileum and locally license IL-17A production by SFB-specific RORγt-expressing T
cells (133, 152). SAAs are also carriers of high-density lipoprotein and retinol (153), and as such
they can potentially deliver these molecules to antigen-presenting cells, providing another am-
plification mechanism for the induction of IL-17 responses within tissues. The microbiota also
promote epithelial cell release of cytokines such as IL-18, IL-25, IL-33, and thymic stromal lym-
phopoietin (TSLP) that can promote innate lymphoid cell responses that in turn can contribute
to the induction and control of commensal-specific T cells (68, 152). Epithelial cells can also
coordinate responses to the microbiota in both the skin and the gastrointestinal tract via local
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release of chemokines involved in T cell tropism, such as CXCL9, CXCL10, and CCL20 (145,
154). Within the skin, accumulation and licensing of commensal-induced Th1 cells, but not Th17
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cells, were controlled by MHC-II-expressing keratinocytes (154). Similarly, studies of the gut bar-
rier demonstrated a role for epithelial cell expression of MHC-II in the accumulation of CD4+
CD8αα+ IELs (155). Much remains to be learned about how structural cells, including epithelial
and stromal cells from distinct compartments, respond to commensals in a way that promotes the
induction and function of commensal-specific responses.
While the default program of immune responses directed toward the microbiota is associated
with the preservation of tissue homeostasis, the fate of commensal-specific T cells is highly con-
textual and can be affected by host activation status, the microenvironment, and the composition
of the microbiota itself. This latter point can be illustrated by the contextual fate of responses
to A. muciniphila (90). A. muciniphila is a member of the microbiota of both mice and humans
that impacts a large array of biological outcomes, ranging from host metabolism to response to
checkpoint therapy (156, 157). A. muciniphila exclusively promotes the generation of Tfh cells in
a gnotobiotic, nine-member bacterial community (90). However, in the context of a complex mi-
crobiota, A. muciniphila–specific T cells can adopt highly diverse fates, including differentiation
into Th1, Th17, and Treg cells (90). Thus, microbiota composition and function can contribute
to the quality of responses directed toward the microbiota, illustrating once again the limitation
of monoassociation studies.
Infections are a highly volatile setting for barrier tissues. During infection, commensal anti-
gens are recognized in an inflammatory context. Furthermore, breach of the intestinal or skin
barrier due to infection allows commensal antigen translocation to ectopic sites. In this context,
commensal-specific T cells can differentiate to an inflammatory phenotype and form memory cells
that are phenotypically and functionally indistinguishable from pathogen-specific T cells (110).
Indeed, CBir1-specific T cells, which remain naive during homeostasis, are activated and adopt T
cell fates consistent with the inflammatory challenge: Toxoplasma gondii infection leads to CBir1-
specific Th1 cell differentiation, while chemically induced colitis induces Th17 differentiation
(110). Barrier tissues are also involved in numerous inflammatory disorders, a phenomenon that
can trigger the induction of aberrant and inflammatory responses to the microbiota. For instance,
under steady-state conditions, Helicobacter hepaticus colonizes the gut without causing inflamma-
tion, a process associated with the induction of both RORγt+ Treg cells and Tfh cells (158). On
the other hand, in the context of defects in tissue regulation, including in Treg cells, the same
microbe can also trigger severe colitis (158–161). Mechanistically, a heightened level of IL-23
together with systemic production of SAAs, as opposed to discrete production in steady state,

www.annualreviews.org • Control of Immunity by the Microbiota 467

 promotes H. hepaticus–specific, pathogenic Th17 responses and expression of a proinflammatory
program, including coexpression of T-bet/RORγt and IFN-γ/IL-17 (152, 162).
It is unknown whether commensal-specific T cells are maintained independent of continuous
cognate antigen stimulation in a manner similar to that of virus-induced tissue-resident memory
T cells or IELs (155, 163). Commensal-specific memory T cells decline steadily over time (110,
164), and the ability of the microbiota to promote true immunological T cell memory at steady
state or in the context of inflammation remains an open question. Perhaps an evolving pool of
specificities within the regulatory and effector T cell compartment allows for the maintenance
of both tissue immunity and tolerance to the microbiota in the face of microbiota shifts and in-
termittent infections. Nonetheless, based on the scope of antigenic load within the microbiota, a
significant fraction of effector and memory cells, including tissue-resident memory T cells, may
be microbiota specific. The implication of this phenomenon is that barrier breach or infection at
barrier sites is likely to occur in the context of broader recall responses against microbiota-derived
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antigens. For instance, within the skin, preexistence of homeostatic Th17 responses to fungal com-
mensals can promote inflammatory responses in the context of subsequent experimental psoriasis
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(147). The long-term fate of microbiota-specific T cells as well as the relative contribution of
memory responses or neo-inflammatory responses to the microbiota in the etiology of inflamma-
tory disorders remains to be addressed.

3.4. Immunoregulatory T Cells

Maintenance of tissue homeostasis in the face of the ability of the microbiota to engage the im-
mune system requires both constitutive (e.g., barrier structures, mucus) and induced immunoreg-
ulatory responses. Indeed, the ability of the microbiota to promote immunity is coupled with its
ability to promote numerous immunoregulatory mechanisms. The balance of these responses de-
fines the tissue threshold of activation. Failure to regulate responses to the microbiota can have
catastrophic consequences for the host, as exemplified in the context of numerous inflammatory
disorders, including inflammatory bowel diseases (165). While regulation of responses to the mi-
crobiota encompasses multiple structural and cellular components, we focus our present discussion
on the role of T cells, and more specifically Treg cells, in these processes.
FOXP3+ Treg cells play a nonredundant role in the maintenance of immunological homeo-
stasis (166). Within the gut, induced Treg cells constrain responses to orally acquired antigens,
including antigens derived from the microbiota. This phenomenon is promoted by a complex net-
work of cells, including specialized antigen-presenting cells, as well as a milieu enriched in TGF-β,
retinoic acid, and, as further discussed, microbiota-derived metabolites (167–170) (Figure 4). It
has been long recognized that oral tolerance, a phenomenon associated with the induction of
FOXP3+ Treg cells (169), cannot be induced in the absence of the microbiota (171). Indeed, sub-
sets of Treg cells are reduced under germ-free conditions or in the context of antibiotic treat-
ment (172–175). Although tools to track commensal-specific responses remain limited, the use
of microbe-specific transgenic T cells supports the idea that within the gut, and in particular the
colon, Treg cells are enriched for TCRs specific for microbiota-derived antigens (54, 158, 176,
177). While in germ-free settings only a few individual microbes promote the induction of effec-
tor responses, a large number of isolates or microbiota-derived consortia are able to promote Treg
cell induction and function (90, 143, 172, 178). This supports the ideas that Treg cell induction
is a dominant feature of microbes associated with health and that these responses are promoted
by microbiota-derived, canonical, and redundant factors. In contrast, microbes that dominate in
the context of inflammatory states such as IBD fail to promote Treg cells when transferred to
mice (91, 179). While IL-10 production by Treg cells plays a dominant role in the gastrointestinal

468 Ansaldo • Farley • Belkaid

 tract, Treg cells use several redundant and complementary mechanisms to constrain reactivity to
the microbiota (166, 180).
The capacity of Treg cells to adapt to specific environments and to respond to tissue-specific
cues contributes to their ability to regulate tissues colonized by the microbiota (166). For instance,
upon migration into the gut epithelial layer, Treg cells lose FOXP3 expression and convert to
CD4+ IELs in a microbiota-dependent manner, a phenomenon that may contribute to the ability
of these cells to regulate this compartment (181). The microbiota also specifically induce a subset
of Treg cells expressing RORγt with a preferential tropism for the colon lamina propria (173, 174,
182). The accumulation of RORγt-expressing Treg cells occurs between two and three weeks after
birth (173, 174), which coincides with weaning associated with a profound immune reprograming
and a shift in microbiota composition (43). This subset of Treg cells has been associated with the
control of aberrant immune responses to specific commensals. For instance, the ability of H. hep-
aticus to promote the induction of RORγt-expressing Treg cells and associated IL-10 constrains
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inflammatory responses to the very same microbe (158). The induction and function of this subset
depend on the expression of the transcription factor C-MAF (158, 183). Of note, in the context
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of H. hepaticus colonization and C-MAF but not RORγt deletion, Treg cell function is impaired
(158). On the other hand, RORγt deletion in FOXP3-expressing cells is associated with either en-
hanced Th2 responses and worm-induced, Th2-mediated pathology (173) or enhanced type 1/17
responses and enhanced susceptibility to experimental colitis (174). Based on the fundamental role
of the microbiota in setting the host immune set point, we could speculate that these differential
outcomes are related to distinct microbiota-associated immune imprinting.
Numerous microbiota-associated factors converge to promote optimal Treg cell induction
and function. For instance, SCFAs, metabolites produced in the colon by bacterial fermenta-
tion of dietary fibers and resistant starch, can promote numerous biological functions, including
Treg cell induction (173, 184–186). As such, microbes endowed with the ability to generate large
amounts of SCFAs, such as consortia of Clostridium strains, can preferentially induce Treg cells
(187, 188). Mechanistically, SCFAs have been proposed to act directly on T cells and indirectly
on macrophages or dendritic cells via histone deacetylase inhibition, G protein–coupled recep-
tors such as GPR43, or both (173, 184–186). Promotion of Treg cells by the microbiota is also
associated with the ability of specific microbes such as Clostridium to promote a TGF-β-rich en-
vironment (187, 189).
Other canonical products resulting from microbiota activity have been recently shown to pro-
mote Treg cell induction. Bile acids are highly abundant in the gut, where they undergo bacterium-
mediated transformation leading to the generation of a large pool of bioactive molecules. Recent
work revealed that diet alteration impacts the level of colonic RORγt+ Treg cells, and a role for
microbial bile metabolites in this phenomenon was proposed (190–192). For instance, isoalloLCA,
a secondary bile acid, directly promotes Treg cell induction via mitochondrial reactive oxygen re-
sponses in T cells (191). Secondary bile acids, which are the products of metabolism of primary
bile acids by the microbiota, can also enhance the ability of dendritic cells to promote Treg cells,
as in the case of isoDCA (190). Because of the fundamental importance of Treg cells in constrain-
ing reactivity to the microbiota, each of these factors is likely to act in a synergistic and redun-
dant manner. Further, it is likely that a large fraction of microbiota-derived products at all barrier
sites have coevolved with the immune system to favor regulatory responses. For instance, specific
microbe-associated molecules such as the B. fragilis–derived capsular factor polysaccharide A can
impact dendritic cell function in a manner that promotes Treg cell induction, and cell surface
polysaccharides of Bifidobacterium bifidum promote the induction of IL-10-producing Treg cells
in a TLR2-dependent manner (193–195).

www.annualreviews.org • Control of Immunity by the Microbiota 469

 In contrast to gut microbes, skin microbes are not essential for the optimal seeding of dermal
Treg cells (151). As shown within the gut, the continuous action of Treg cells within the skin con-
trols reactivity to commensals acquired later in life. For instance, in mice with a specific defect
in Treg fitness within the skin, RORγt-expressing, commensal-specific T cells produce aberrant
type 2 cytokines, a phenomenon that can have consequences in the etiology of skin inflammatory
disorders (121). As discussed in Section 2.3, neonatal colonization of the skin with S. epidermidis
can promote accumulation of commensal-specific FOXP3+ Treg cells, thereby preventing inflam-
matory reactivity to the same microbe later in life (54). Whether this phenomenon applies only to
specific microbes encountered early in life remains to be addressed. A recent study also supported
the idea that microbes potentially able to cause disease escape such regulatory imprinting (196).
For instance, induction of IL-1β in response to Staphylococcus aureus–associated α-toxin actively
inhibits the induction of Treg cells in neonates (196), which may contribute to the maintenance
of immune awareness of these microbes later in life. Importantly, many other cell types involved
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

in immune surveillance also help enforce immune tolerance in response to the microbiota, ei-
ther indirectly by supporting Treg cell induction and function (197) or directly by secreting im-
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munomodulatory factors (198–200).

Altogether these findings support major roles for the microbiota in shaping the repertoire,
number, and activation of Treg cells and in maintenance of host-microbe mutualism at barrier
sites. However, much remains to be learned about the molecular basis of host-microbe interactions
within individual barrier sites and the overall dynamic of effector versus regulatory responses
required to maintain or restore host-microbiota homeostasis.

4. CONCLUSIONS AND PERSPECTIVES

Our increasing integration of the microbiome in our understanding of host physiology has trans-
formed our understanding of the immune system and its relationship with its symbionts. Not only
do immune cells and the microbiota help control infections and malignancy but the extraordinary
plasticity and motility of immune cells and their reliance on the highly dynamic microbiota also
bridge virtually all physiological systems, making the immune system and microbiota central reg-
ulators of host homeostasis.
This novel understanding also brings unique challenges. Exploration of the relationship be-
tween the microbiota and the immune system in health and disease requires the integration of
numerous other branches of biology, including biochemistry, cellular biology, genetics, and mi-
crobiology. Emerging evidence reveals that harnessing the microbiota for therapeutic purposes
may be a valid and promising approach. For instance, in the gut, microbe-mediated therapy in
the form of fecal transplantation has been successful for Clostridium difficile infections (201), and
Lactobacillus plantarum has been successful in preventing neonatal sepsis (202). Harnessing the im-
munomodulatory or antimicrobial properties of particular members of the microbiota also has
great potential. Furthermore, prebiotic intervention or local alterations in specific nutrients may
have a marked impact on the composition or function of microbiota at all barrier surfaces and—
when rationally designed—could promote the expansion of microbes endowed with regulatory or
protective properties. However, it is important to remember that mechanistic exploration of im-
mune system–microbiota interactions is relatively recent, and despite the extraordinary diversity
of microbial products and antigens, only a few instances of immune recognition of microbiota-
derived antigens or metabolites have been identified. Further exploration of host-microbiota in-
teractions is groundwork for the formidable task of developing novel approaches and unique tools
for the next generation of therapeutics.

470 Ansaldo • Farley • Belkaid

 DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
This work was supported by the Division of Intramural Research of the National Institute of
Allergy and Infectious Diseases (NIAID). We thank all the members of the Belkaid laboratory
and in particular Drs. Ai Ing Lim, Nick Collins, and Michael Constantinides for critical reading
of the manuscript and helpful discussions. We sincerely apologize to our colleagues for the work
we could not include in the present review because of space constraints.

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prevent sepsis among infants in rural India. Nature 548(7668):407–12

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Annual Review of
Immunology

Volume 39, 2021

Contents
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

The Habitat Filters of Microbiota-Nourishing Immunity

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Brittany M. Miller and Andreas J. Bäumler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1

Current Concepts and Advances in Graft-Versus-Host Disease Immunology
Geoffrey R. Hill, Brian C. Betts, Victor Tkachev, Leslie S. Kean,
and Bruce R. Blazar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19
Cytokine Regulation and Function in T Cells
Chen Dong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51
The Antisocial Network: Cross Talk Between Cell Death Programs in Host
Defense
Annelise G. Snyder and Andrew Oberst p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p77
The Shaping of a B Cell Pool Maximally Responsive to Infections
Nicole Baumgarth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 103
Dendritic Cells Revisited
Mar Cabeza-Cabrerizo, Ana Cardoso, Carlos M. Minutti,
Mariana Pereira da Costa, and Caetano Reis e Sousa p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131
Group 2 Innate Lymphoid Cells: Team Players in Regulating Asthma
Noe Rodriguez-Rodriguez, Mayuri Gogoi, and Andrew N.J. McKenzie p p p p p p p p p p p p p p p p p 167
The Ins and Outs of Central Nervous System Inflammation—Lessons
Learned from Multiple Sclerosis
Valeria Ramaglia, Olga Rojas, Ikbel Naouar, and Jennifer L. Gommerman p p p p p p p p p p p p p 199
Genetics of Pediatric Immune-Mediated Diseases and Human Immunity
Erica G. Schmitt and Megan A. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227
Microglia and Central Nervous System–Associated Macrophages—From
Origin to Disease Modulation
Marco Prinz, Takahiro Masuda, Michael A. Wheeler, and Francisco J. Quintana p p p p p p 251
Epigenetic Remodeling in Innate Immunity and Inflammation
Qian Zhang and Xuetao Cao p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279

viii
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Origins, Biology, and Diseases of Tissue Macrophages

Nehemiah Cox, Maria Pokrovskii, Rocio Vicario, and Frederic Geissmann p p p p p p p p p p p p p p 313
Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells
Tyler J. Ripperger and Deepta Bhattacharya p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Immunosensation: Neuroimmune Cross Talk in the Skin
Masato Tamari, Aaron M. Ver Heul, and Brian S. Kim p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Mitochondrial Metabolism Regulation of T Cell–Mediated Immunity
Elizabeth M. Steinert, Karthik Vasan, and Navdeep S. Chandel p p p p p p p p p p p p p p p p p p p p p p p p p 395
Natural Killer Cells: From Innate to Adaptive Features
Adriana M. Mujal, Rebecca B. Delconte, and Joseph C. Sun p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

Control of Immunity by the Microbiota

Eduard Ansaldo, Taylor K. Farley, and Yasmine Belkaid p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 449
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Control of RNA Stability in Immunity

Shizuo Akira and Kazuhiko Maeda p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 481
Glycans in Immunologic Health and Disease
Julie Y. Zhou and Brian A. Cobb p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
IL-17 in the Pathogenesis of Disease: Good Intentions Gone Awry
Saikat Majumder and Mandy J. McGeachy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 537
Tissue Homeostasis and Inflammation
Matthew L. Meizlish, Ruth A. Franklin, Xu Zhou, and Ruslan Medzhitov p p p p p p p p p p p p p 557
Insights Gained from Single-Cell Analysis of Immune Cells in the Tumor
Microenvironment
Xianwen Ren, Lei Zhang, Yuanyuan Zhang, Ziyi Li, Nathan Siemers,
and Zemin Zhang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 583
The Innate Immune Response to Mycobacterium tuberculosis Infection
Mariëtta M. Ravesloot-Chávez, Erik Van Dis, and Sarah A. Stanley p p p p p p p p p p p p p p p p p p p 611
Immune System Investigation Using Parasitic Helminths
Bonnie Douglas, Oyebola Oyesola, Martha M. Cooper, Avery Posey,
Elia Tait Wojno, Paul R. Giacomin, and De’Broski R. Herbert p p p p p p p p p p p p p p p p p p p p p p p p 639
Trained Immunity: Reprogramming Innate Immunity in Health and Disease
Siroon Bekkering, Jorge Domínguez-Andrés, Leo A.B. Joosten,
Niels P. Riksen, and Mihai G. Netea p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 667
Production and Function of Immunoglobulin A
Timothy W. Hand and Andrea Reboldi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 695

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Eosinophil Knockout Humans: Uncovering the Role of Eosinophils

Through Eosinophil-Directed Biological Therapies
Elizabeth A. Jacobsen, David J. Jackson, Enrico Heffler, Sameer K. Mathur,
Albert J. Bredenoord, Ian D. Pavord, Praveen Akuthota,
Florence Roufosse, and Marc E. Rothenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 719
Dendritic Cell Regulation of T Helper Cells
Xiangyun Yin, Shuting Chen, and Stephanie C. Eisenbarth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 759
Decoding Cell Death: From a Veritable Library of Babel to Vade Mecum?
Lindsey D. Hughes, Yaqiu Wang, Alexandre P. Meli, Carla V. Rothlin,
and Sourav Ghosh p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 791
Annu. Rev. Immunol. 2021.39:449-479. Downloaded from www.annualreviews.org

Indexes
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Cumulative Index of Contributing Authors, Volumes 29–39 p p p p p p p p p p p p p p p p p p p p p p p p p p p 819

Cumulative Index of Article Titles, Volumes 29–39 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 826

Errata
An online log of corrections to Annual Review of Immunology articles may be found at
http://www.annualreviews.org/errata/immunol

x Contents