Cell-Mediated Immunity

With Prof. Peter J. Delves

Learning Objectives

• Compare ab and gd T cells.

• Analyse the different populations of ab T cells.

• Identify the role of cytokines in health and disease.

Cell-Mediated Immunity

Immunity provided by cytotoxic T-cells and by T helper cell-mediated

activation of macrophages.

Required to defeat intracellular pathogens, which are hidden from

the effects of antibodies and complement.
Cell-Mediated Immunity

Cytokines

Activated cytotoxic T-cell (Tc, CTL)

Helper T-cell (Th)

Activated macrophage
ab and gd T-cells

ab T-cell gd T-cell

TCR TCR

a-chain b-chain g-chain d-chain

Recombination of TCR Recombination of TCR

Diversity created by a-chain and b-chain genes g-chain and d-chain genes
in the thymus in the thymus
Antigens alone,
Peptides presented lipoprotein and glycolipids
Recognize
by MHC molecules presented by the MHC-like
molecule CD1
gd T cells

• Appear to have a distinct role TCR

complementary to that of αβ T cells.
g-chain d-chain
• Contains <5 % of T cells, and are present
mostly in the gut mucosa, skin, lungs and
uterus.

• Can directly recognize microbial pathogens

and damaged or stressed host cells.
gd T cells

Examples of recognition: TCR

• Direct recognition of phosphoantigens from
Mycobacterium tuberculosis and Plasmodium g-chain d-chain
malariae, without a requirement for antigen
processing.

• Direct recognition of the MHC-like non-

peptide-binding molecules MICA or MICB,
or of CD1 irrespective of any lipoprotein or
glycolipid antigen.
Structure of the T cell Receptor (TCR)

NH2 NH2

a-chain V V b-chain
or or
g-chain d-chain

C C

COOH COOH
T cell Receptor (TCR) interaction with pMHC

The V domains of the TCR

Antigenic peptide

a-helical region
of MHC binding
the peptide

MHC (class I)
Nairn, Roderick: Immunology for Medical Students. 2nd Edition. Elsevier. 2007. Fig 7.7
ab T cells
CD4 CD8
Th1 Th2 Th17 Tfh Treg Tc

Transcription T-bet GATA3 Bcl-6 Foxp RUNX

RORgt Bcl-6
factors STAT4 STAT6 3 3

IL-4 Perforin,
IFNg TGFb
IL-5 IL-17 IL-21 granzymes,
Produce IL-2 IL-10
IL-6 IL-22 ICOS FasL,
TNFb IL-35
IL-13 cytokines

Help CTL
& macro- Help
Suppress Kill
Primary phages Help B cells, Promote germinal
immune infected
function (and some inhibit Th1 inflammation center
responses cells
B cells), B cells
inhibit Th2
MAIT cells

Musocal-associated invariant T cells

Up to 10% of circulating T cells and also present in liver, mucosal and other tissues

Invariant TCR α chain paired with restricted repertoire of TCR β chains

Most are C8+

Recognise antigens presented by the nonpolymorphic MHC class I-like molecule MR1

Rapid, innate-like, anti-microbial response

Release cytokines including IFNγ, TNFβ, IL-2, IL-17, IL-22

Th0 Cells

IL-12, IFNg Th1

The cytokines secreted by DC depend

on which cell surface, cytoplasmic or
endosomal PRRs are activated. Th0

Thus, optimal response determined IL-4

Th2
by the PAMPs.

Also influenced by activation of other

cell types, e.g., NK cell secretion of
IFNg. Th17
IL-6, IL-23
TGFb
Th1 Cells

IL-2 IFNg IL-2 IFNg

Tc Macrophage B Th2
Th1 Activation of Cytotoxic T cells

Th1 cell Activation of Tc

IL-2
IL-2 receptor

pMHCII pMHCI

DC
Th1 Activation of Cytotoxic T cells

Th1 cell Activation of Tc Activated Tc

IL-2
IL-2 receptor

Seek out
infected cells

DC
Th1 Activation of Macrophages

Macrophage containing Macrophage microbicidal

Th1 cell phagocytosed bacteria mechanisms kill bacteria

Activation
of macrophage
IFNg IFNg
receptor
Th2 Cells

IL-6 IL-5 IL-4

IL-5 IL-4

B Eosinophil Th1
Regulatory T-cells

Suppress
immune
responses
Cell surface
CTLA-4 & LAG-3

IL-10
TGFb

Eosinophil Basophil Mast cell Th Tc DC

Cytotoxic T-cells

1. Kill infected or tumor cells

2. Secrete cytokines
• Tc1: IFNg, etc.

• Tc2: IL-4, etc.

CD8 Tc
Killing by Cytotoxic T-cells

FasL Granzymes
Fas
pMHCI Perforin
Caspase Caspase
activation & activation &
apoptosis apoptosis
Removal of Killed Cells by Macrophages

Tc Virus- Apoptosis Phagocytosis

infected
cell

Phosphatidylserine
receptor

Internal Externalized
phosphatidylserine phosphatidylserine
Intraepithelial Lymphocytes

Villus
• Resident within the intestinal epithelium

• One of the first lines of defence Lamina Absorptive

propria epithelial
• Mixed population of antigen- cell
experienced T-cells Basement
membrane IEL
• gd T-cells

• ab T-cells Goblet cell

• Some CD4+, some CD8+

Crypt
Paneth cell
Intraepithelial Lymphocytes

Villus
• Resident within the intestinal epithelium

• One of the first lines of defence Lamina Absorptive

propria epithelial
• Mixed population of antigen- cell
experienced T-cells Basement
membrane IEL
• gd T-cells

• ab T-cells Goblet cell

• Some CD4+, some CD8+

Crypt
Paneth cell
Cytokines

Small ( ~8 80 kDa) secreted proteins that act as messengers between cells.

Main groups of cytokines are:

• Interleukins

• Colony-stimulating factors

• Chemokines

• Interferons

• Tumor necrosis factors

Cytokines
They have multiple functions, including control of hematopoiesis and immune responses.

They bind to specific cytokine receptors, which initiate intracellular signalling.

Signalling leads to or expression of genes:

• Encoding other cytokines

• Encoding cell surface molecules

• Encoding secreted molecules

• Controlling cell proliferation

• Controlling cell differentiation

• Controlling cell survival

Cytokines Interferons

Inhibition of viral replication

Type I IFNa, IFNb:

• Produced by most nucleated cells of the body

Type II IFNg:
• Produced by NK cells, Th1 cells and Tc1 cells (immune interferon)

• Promotes production of Th1 cells

• Inhibits production of Th2 cells

• Activates macrophages

• Increases MHC class I and class II expression

Cytokines Interleukins

• Act between leukocytes

• Approx 40 different interleukins

Interleukin Main sources include: Main activities include:
IL-1 Macrophages and dendritic cells Pro-inflammatory
IL-2 Th1 cells Promotes T & B-cell proliferation
Promotes Th2 cell differentiation, class
IL-4 Th2 cells
switches B cells to IgE production
IL-10 Treg cells Anti-inflammatory
IL-12 Macrophages and dendritic cells Promotes Th1 cell differentiation
IL-13 Th2 cells Promotes B-cell proliferation
IL-17 Th17 cells Pro-inflammatory
IL-22 Th17 cells Pro-inflammatory
Cytokines Colony Stimulating Factors

Secreted by a variety of cell types, including bone marrow stromal cells

(e.g. fibroblasts and macrophages)

Granulocyte-macrophage
Acts early in myeloid development
colony-stimulating factor (GM-CSF)

Monocyte/macrophage colony-stimulating
Induces monocyte differentiation
factor (M-CSF)

Granulocyte colony-stimulating factor

Induces granulocyte differentiation
(G-CSF)
Chemokines
Chemotactic cytokines, but with multiple other effects. Secreted by many different types of cells.

Four families grouped according to arrangement of cysteines in their structure:

Family Example

C Lymphotactin

CC RANTES

CXC IL-8

CX3C Fractalkine
Tumor Necrosis Factors

TNFa, TNFb (lymphotoxin)

Produced by multiple cell types, including macrophages, monocytes, T cells, B cells, NK cells

Multiple effects including:

Macrophage activation

Induction of endothelial cell adhesion molecules in acute inflammation

Stimulation of production of other cytokines

Transforming Growth Factors

TGFb mainly inhibitory

• Secreted by Tregs and monocytes

• Inhibits macrophage and dendritic cell activation

• Inhibits B and T cells

Cytokines Functional Modes

Autocrine

Paracrine
Cytokine Network Interactions

Th1 Macrophage Th1

Cascade

Example IFNg IL-12 IFNg, IL-2, TNFb

Cytokine Network Interactions
Pleiotropism Redundancy Synergism Antagonism

Example IL-2 IL-4 and IL-5 TNFa and IFNg IL-4 and IFNg
• T cell • B cell • Inhibition of • Class switch to
proliferation proliferation viral replication IgE

• B cell
proliferation

• NK cell
activation
Cytokine Receptor Signaling

Cell membrane
Cytokine Receptor Signaling

JAK = janus kinase

Dimerisation of cytokine receptor STAT = signal
transducer and
activator of
Cell membrane transcription

JAK JAK
P P P P
STAT STAT

STAT
P P STAT dimerization
STAT

Gene transcription
Therapeutic Blocking of Pathological Cytokines

Cytokine
Blocker,
e.g., monoclonal
antibody Cytokine receptor
Therapeutic Blocking of Pathological Cytokines

Activity Indications
Anti-IL-1β Cryopyrin-associated periodic syndromes, juvenile idiopathic arthritis

Anti-IL-6 Multicentric Castleman disease

Anti-IL-12 and Plaque psoriasis, p

anti-IL-23

Anti-BLyS Systemic lupus erythematosus

Anti-TNFα (antibody or Rheumatoid arthritis, plaque psoriasis, ulcerative colitis,

soluble receptor) ankylosing spondylitis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis

IL-1RA RA, cryopyrin-associated periodic syndromes

Anti-IL-2 receptor Acute kidney rejection
Rheumatoid arthritis, polyarticular or systemic juvenile idiopathic arthritis, Giant
Anti-IL-6 receptor cell arteritis, Systemic sclerosis-associated interstitial lung disease, Cytokine
release syndrome
Therapeutic Cytokines

Cytokine

Cytokine receptor
Therapeutic Cytokines
Cytokine Effect Indications
Chronic hepatitis C, AIDS-related Kaposi sarcoma,
Antiproliferative hairy cell leukemia,
IFNα
Antiviral chronic myelogenous leukemia, metastatic melanoma
Antiproliferative
IFNβ Relapsing multiple sclerosis
Antiviral
Control of infection in chronic granulomatous disease,
Immunostimulatory delay of progression in severe malignant
IFNg
Antiviral osteopetrosis
Metastatic renal cell carcinoma and metastatic
IL-2 Immunostimulatory
melanoma
Prevention of thrombocytopenia after
IL-11 Thrombopoietic growth factor
myelosuppressive chemotherapy
Reversal of neutropenia after chemotherapy or
G-CSF Stimulates granulocyte production radiotherapy
Stimulates granulocyte and Reversal of neutropenia after chemotherapy or
GM-CSF radiotherapy
monocyte/macrophage production
Learning Outcomes

✓ To compare ab and gd T cells.

✓ The different populations of ab T cells.

✓ The role of cytokines and health and disease.

List of References

Immunology for Medical

Students, 2nd Edition
Nairn