Prelim - Adaptive Immune Response
Prelim - Adaptive Immune Response
1. Faster
I. Introduction
2. Larger
II. Adaptive Immune response
a. Phases of Adaptive Response 3. More specific
III. T-cell Differentiation 4. Less damage to self
IV. T- cell activation and effector function
V. T-helper sub populations and function 1. Antigen Recognition
VI. B- cell expansion and differentiation
PHASES OF ADAPTIVE RESPONSE
VII. The role of T-cell in Adaptive Immune
Response 2. Lymphocyte Activation
VIII. The role of B-cell in adaptive Immune 3. Antigen Elimination
Response 4. Contraction (Homeostasis)
IX. Laboratory Identification of Lymphocytes 5. Memory
INTRODUCTION
Adaptive immune response:
- Host response to foreign agents that
depends on T and B lymphocytes and is
characterized by specificity, memory, and
recognition of self versus nonself.
1
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
ADAPTIVE IMMUNITY Differentiation of lymphocytes:
- A type of resistance characterized by: ● Appears to take place very early in fetal
• Specificity for each individual pathogen or development.
microbial agent ● Essential to the acquisition of
• The ability to remember a prior exposure immunocompetence by the time the infant is
• An increased response to that pathogen upon born.
repeated exposure
- A more tailored response; takes a longer time to Progenitors of T and B cells - appear in the FETAL
be activated, but more specific and longer lasting. LIVER (at 8 weeks of pregnancy)
1. T cells
2
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
● As thymocytes travel through the thymus,
there is an orderly TCR consists of two specific chains:
● rearrangement of the genes coding for the 1. alpha (α) chains
antigen receptor. 2. beta (β) chains
● At the same time, distinct surface markers Both contain variable regions that recognize specific
appear during specific stages of antigens.
development. ● These 2 chains occur in a complex with 6 other
chains that are common to all T cells.
MATURATION - an elaborate process that ● CD3/TCR complex - the combination of the 8
takes place over a 3-week period as cells filter chains
through the cortex ● 6 chains of the nonspecific CD3 portion of
to the medulla. the complex - assist in signaling when an
antigen binds to the T cells.
Thymic stromal cells include: These chains occur in 3 pairs:
(all play a role in T-cell development) ● delta-epsilon (δ–ε) chain
● epithelial cells ● gamma-epsilon (γ–ε) chain
● macrophages ● a tau-tau (ζ–ζ) chain (in the cytoplasm of the
● fibroblasts cell)
● dendritic cells
● The α and β chains of the TCR - coded for by the
● Interaction with stromal cells under the selection of certain gene segments and deletion
influence of cytokines (esp. IL-7) = critical of others in a random fashion.
for growth and differentiation.
3
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
● MHC RESTRICTION - selection of thymocytes
10% of thymocytes: that will only interact with the MHC antigens
found on host cells.
● Any thymocytes that have either a very low or a
● Rearrange and express two other chains—
very high affinity for self-MHC antigens = DIE by
● gamma (γ) and delta (δ)—when there is NOT a
apoptosis.
productive rearrangement of DNA coding for a β
● NEGATIVE SELECTION (NS) - second
chain.
selection process taking place among the
● They proceed on a different developmental
surviving DP T cells, in the corticomedullary
pathway, remain NEGATIVE for both CD4 and
region and the medulla of the thymus
CD8.
Note: Medullary epithelial cells express a
● As mature T cells, they appear to represent the
dominant T-cell population in the skin, intestinal
wide variety of self-antigens
● Strong reactions with self-peptides other than
epithelium, and pulmonary epithelium. (Tasks
MHC antigens TRIGGERS apopotosis.
include wound healing and protection of the
epithelium)
CLONAL DELETION - process of elimination of
● Capable of recognizing antigens WITHOUT being
clones of T cells that would be capable of an
presented by MHC proteins (to represent as an
autoimmune response.
important bridge between innate & adaptive
Note: Only 1% to 3% of the DP thymocytes in the
immunity)
cortex survive!
POSITIVE SELECTION
● Allows only DP cells with functional TCR
receptors to survive.
● T cells must recognize foreign antigen in
association with class I or class II MHC MATURE T-CELLS
molecules. ● Survivors of selection exhibit only one type of
● When thymocytes bind to self-MHC antigens in marker, either CD4 or CD8 (may depend on
the cortex by means of the newly formed TCR which MHC protein the cell interacts with, how
receptors, an enzyme cascade involving a group strongly they react, and to which cytokines they
of enzymes called kinases is activated. are exposed).
● Enzyme activity causes changes in cell shape ● CD4+ T cells - recognize antigen along with
and motility that lead to increased cell survival. class II MHC protein; mainly T helper cells
● CD8+ T cells - interact with antigen and class I
MHC proteins; cytotoxic T cells
4
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
● the CD4 receptor are mainly T helper (Th) cells,
whereas the CD8+ population consists of ✔ Th17 Cells
cytotoxic T cells. -produce IL-17and IL-22 (both of these cytokines
Note: T cells 2/3 (CD4); 1/3 (CD8) can increase inflammation and joint destruction)
- associated with autoimmune diseases such as
SUBPOPULATION OF T-CELLS rheumatoid arthritis, multiple sclerosis, and
inflammatory bowel disease.
✔ Th9 Cells
5
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
STAGES IN CELL DIFFERENTIATION
Pro- B Cells
6
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
marrow) to differentiate common lymphoid Surrogate light chain – consist of two short
precursors in to pro-B cells: polypeptide chains that are noncovalently associated
o E2A w/ each other, along w/ two shorter chains, Ig-α
o EBF (early B-cell factor) and Ig-β, w/c are signal-transducing subunits.
o IFR8 (Interferon regulatory
Pre-B cell receptor (pre-BCR) – formed by the
factors)
combination of two heavy chains along with Ig-α, Ig-
o PAX5 (paired bpx protein 5
β and surrogate light chain
1st step in the pro B-phase – the rearrangement
Pre-B cells expressing the μ heavy chains in
of genes that code for the heavy and light chains of
association w/ surrogate light chains survive and
an antibody molecule.
proceed to further differentiation.
Rearrangement of the DNA is similar to the
Signaling through pre-B receptors formed
process that ccurs in T cells.
stimulates a bust of clonal expansion.
Chromosome 14 – heavy chains of antibody are
coded
μ chains – the first heavy chains synthesized, w/c ● Immature B cells are distinguished by
belongs to the class of IgM. complete IgM antibody molecules on the
cell surface.
Accumulate in the cytoplasm
○ This indicates that rearrangement
Can be expressed by Pre-B cells on the cell
of the genetic sequence coding for
surface, accompanied by surrogate light
chain molecule. light chains on either
chromosome 2 or 22 has taken
place by this time.
7
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
○ Rearrangement commits a cell to ■
In other words, immature B
produce antibodies specific for cells that cannot recognize
particular antigens or groups of the self do not pass the
related antigens. negative selection.
○ IgM molecules thus serve as the ○ Thus, many B cells producing
receptor for antigen. antibody to self-antigens undergo
● Variable regions, which occur on both the cell death/apoptosis.
light and heavy chains, determine the ● It is estimated that more than 90% of B
antigen specificity. cells die in this manner without leaving the
● Preexisting diversity of receptors for antigen bone marrow.
- hallmark of the adaptive immune system. ● The elimination of B cells that bear self-
○ The capability to respond to a reactive receptors is known as central
specific antigen is built in before a B tolerance.
cell ever encounters an antigen. Immature B cells that survive this selection process
● Once surface immunoglobulins appear, µ leave the bone marrow and proceed to the
chains are no longer detectable in the spleen, where they become mature B cells.
cytoplasm. Mature B Cells
● Other surface proteins that appear on the
immature B cell include: ● Maturation is in the spleen, where they
○ CD21 become marginal zone B cells or follicular B
○ CD40 cells.
○ class II MHC molecules. ● Marginal B cells stay in the spleen for it
● CD21 acts as a receptor for a breakdown to respond quickly to any blood-borne
product of the complement component C3, pathogens they may come into contact
known as C3d. with.
● The presence of the CD21 receptor ● Follicular B cells migrate to lymph
enhances the likelihood of contact between nodes and other secondary organs.
B cells and antigens because antigens ○ Unlike marginal B cells staying in the
frequently become coated with complement spleen, follicular B cells are
fragments during the immune response. constantly recirculating
● CD40 and class II MHC are important for throughout the secondary lymphoid
interaction of B cells with T cells. organs.
● At this stage, there is evidence that self- ● In addition to IgM, all mature B cells
antigens give a negative signal to immature exhibit immunoglobulin D (IgD) on their
B cells. surface.
○ Immature B cells that tightly bind ○ Both IgM and IgD have the same
self-antigens through cross-linking of specificity for a particular antigen or
surface IgM molecules receive a group of antigens. These surface
signal to halt development, resulting immunoglobulins provide the
in arrested maturation and cell primary activating signal to B cells
death (negative selection). when contact with antigen takes
place.
8
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
● IgD is not required for B-cell function but ● Plasma cells in other places DO NOT
may prolong the life span of mature B DIVIDE and, after several days of antibody
cells in the periphery. production, they die without further
○ Unless contact with antigen occurs, proliferation.
the life span of a mature B cell is
typically only a few days. THE ROLE OF T CELLS IN THE ADAPTIVE
● If, however, a B cell is stimulated by IMMUNE RESPONSE
antigen, it transforms to a blast stage that
eventually forms memory cells and APCs (macrophages and dendritic cell)
antibody-secreting plasma cells. This - are first activated during the innate immune
process is known as the antigen- response through their pattern recognition
dependent phase of B-cell development. receptors.
Class I MHC - presents antigen that is from
● The production of antibodies by plasma cells
intracellular pathogens such as viruses to
is called humoral immunity. CD8+ T cells.
Class II MHC - presents antigen from
Plasma Cells extracellular pathogens such as bacteria
processed by a phagocytic cell to CD4+ T
● Plasma cells are spherical or ellipsoidal cells.
● Between 10 and 20 µm. T cells - circulate continuously through the
● They are characterized by abundant bloodstream, lymph nodes, and
cytoplasmic immunoglobulin and little secondary lymphoid tissue; each naïve or
to no surface immunoglobulin. unstimulated T cell circulates from the lymph
nodes to the blood and back again within 12
● The nucleus is eccentric or oval with
to 24 hours; have either CD4 or CD8 on
heavily clumped chromatin that stains their cell surface.
darkly. CD4+ T cells – also known as Th cells
● An abundant endoplasmic reticulum CD8+ T cells – also called cytotoxic T
and a clear well-defined Golgi zone are cells (Tc)
present in the cytoplasm.
● Plasma cells represent the most fully ACTION OF HELPER CELLSS
differentiated lymphocyte
● MAIN FUNCTION: antibody production. 1st signal: CD4+ T cell encounters an
● They are not normally found in the blood; antigen along with a class II MHC molecule
rather, they are located in germinal and binds by using its antigen receptor. CD4
centers in the peripheral lymphoid acts as a co-receptor to stabilize binding.
organs or in the bone marrow. 2nd signal: binding of CD28 on the T cell
with CD80 and CD86 found on APCs.
○ In the bone marrow, plasma cells
Within 1 to 2 days after antigen recognition
can survive in niches surrounded by has occurred, T lymphocytes are
stromal cells. transformed into large activated blast cells
○ Stromal cells provide chemical that are characterized by polyribosome-
stimulation by cytokines, which filled cytoplasm.
allow plasma cells to be long-lived The two main subsets of Th cells, Th1 and
and continually produce antibodies. Th2, secrete different types of cytokines and
affect different classes of cells.
9
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
o Th1 subset - secretes IL-2, usually within 30 minutes of
interferon-gamma (IFN-γ) and TNF- contact.
β, which are responsible for the Granules within cytotoxic T cells contain two
activation of cytotoxic T lymphocytes different types of toxins: granzymes and
and macrophages. perforins.
o Th2 cells - secrete interleukins that Granzymes - are a class of enzymes called
regulate B-cell activity. serine proteases; enter through the pores;
Most antigens encountered in the body are do not directly break down DNA , but they
so-called T-dependent antigens, meaning activate a nuclease that destroys the target
that T-cell help is required in order for B cells cell DNA as well as any viral DNA that may
to respond to antigen. be contained inside it; also activate enzymes
T memory cells - arise early in the course in the target cell that disrupt the cell’s
of an immune response; may arise mitochondria.
independently from effector cells or they may Perforins - are pore-forming proteins that
arise as soon as the original T cell is insert themselves into the target cell
stimulated. membrane; insert themselves into the target
o Have a higher affinity for antigen cell membrane and polymerize, forming
than unstimulated T cells pores in the membrane.
o Able to proliferate sooner than naïve
T cells, express a broader array of THE ROLE OF B CELLS IN THE ADAPTIVE
cytokines, and appear to persist for IMMUNE RESPONSE
years.
10
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
CD25 - found on both activated T and B cells
and which acts as a receptor for IL-2.
LABORATORY IDENTIFICATION OF
IL-2 - a growth factor produced by T cells.
LYMPHOCYTES
Daughter cells of proliferating B cells -
either migrates into the T-cell zone in lymph
nodes and differentiates into plasma cells Identification of lymphocytes as either T cells or B
that secrete IgM in about 4 days or they cells - useful in diagnosis of any of the following
enter B-cell follicles to form germinal centers. states:
B cells - undergo further differentiation ● Malignancies such as leukemias and
under the influence of follicular Th cells. The lymphomas
CD40 on B cells must interact with CD40L on ● Immunodeficiency diseases involving either
Th cells in order for germinal center T or B cells or both; and acquired
formation to occur. immunodeficiency disease (AIDS).
Memory cells - are progeny of B cells that
have been exposed to antigen; they are In some immunodeficiency diseases (X-linked
characterized by a long life span and a rapid hypogammaglobulinemia):
response to second exposure to the ● B cells are frequently absent
triggering antigen; they are similar in In severe combined immunodeficiency disease
appearance to unstimulated B cells, but they (SCID):
remain in an activated state for months or ● Both T and B cells are either absent or
years, ready to respond to the initial antigen. present in very low
CD27 - is used as a marker to identify numbers.
memory cells because they are similar in
appearance to mature B cells. Assays for CD4+ T cells - useful in evaluating the
stage of infection; because HIV infects and
RESPONSE TO T-INDEPENDENT ANTIGENS progressively kills CD4+ T cells
11
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna
o CD19, CD20, CD22, and surface
immunoglobulin on B cells
● Fluorescent antibodies - used to screen for
subpopulations, such as B cells, Th cells, and T
cytotoxic cells.
● Each antibody has a different fluorescent tag.
● Some point-of-care testing has been developed
using either fluorescent or antibody-labeled
beads => measure the CD4 count and reported
as a percentage of the total T-cell count.
12
Lakim, Maranan, Bayquen, Balboa, Peroy, Martirez, Vale, Landiang Salendab, Sampulna