SUMMARY

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SUMMARY

• Membrane bound T cell receptors on T lymphocytes
  detect microbial antigens presented by MHC
  molecules.

2. Both TCR chains contribute to MHC and antigen
recognition and the TCR does not encode effector
functions.
3. V-D-J rearrangements in T lymphocyte
precursors in the thymus select for TCRs that
recognize MHC and do not recognize self-antigens.
4. Two signals are required for T lymphocyte
activation. If T cells only bind MHC-antigen
complexes in the absence of a second signal, the
T cell becomes anergic.
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TODAY
CELL-MEDIATED IMMUNE RESPONSES Chapter 5. Pages
83 - 100
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Cell-mediated immune responses respond to
intracellular microbes.
Such microbes can arise in several ways.
Typically, macrophages engulf and destroy
microbes.
However, some microbes (e.g. Listeria
monocytogenes, Legionella pneumophila) survive
within phagocytes.
Intracellular microbes can replicate with the
cytoplasm of host cells, where they are protected
from microbicidal activities.
Alternatively, many viruses enter host cells
through cell surface receptors.
The main function of T lymphocytes is to destroy
such intracellular microbes. CD4 T lymphocytes
also help B cells produce antibodies.
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ALL T CELL RESPONSES INTERACTIONS WITH OTHER HOST
CELLS
As T cells require peptides presented in the
context of MHC molecules, T cells only respond to
antigens associated with other cells.
The involvement of CD4 or CD8 in TCR -
MHC-peptide recognition determines the type of T
cell response induced by the antigen.
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PHASES OF T CELL RESPONSES
T cell responses occur in a defined series of
steps designed to increase the number of
antigen-specific T cells and stimulate their
conversion to effector cells.
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Remember T cells and antigens are concentrated
in lymph nodes to maximize the likelihood of TCR
- Antigen interactions. Thus, T cells initially
encounter antigens in the peripheral lymphoid
organs.
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T CELL ACTIVATION
5. As the invading microbe is destroyed the
stimulii that triggered T cell expansion
disappear, resulting in a decline of the
population of the responding clone.
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ANTIGEN RECOGNITION
T cell responses require multiple interactions
between the activated T cell and the antigenic
peptide presenting host cell.
A critical step is the recognition of MHC-peptide
complexes by TCR and CD8 or CD4.
Several other proteins are involved in
TCR-MHC-peptide interactions. These molecules are
referred to as accessory molecules.
Accessory molecules have three functions
recognition, signaling and adhesion.
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ANTIGEN RECOGNITION
HOST CELL
APC
1. Microbial peptides are captured from the
extracellular millieu by APC.
1. Cytoplasmic microbes grow in susceptible host
cells.
2. Processed peptides are presented on the
surface by class II MHC molecules.
2. Processed peptides are presented on the
surface by class I MHC molecules.
3. TCR binds the MHC-peptide complex.
3. TCR binds the MHC-peptide complex.
4. Formation of a stable TCR-MHC-peptide complex
requires binding of CD4 to MHCII and CD8 to MHC
class I molecules.
The CD4 and CD8 co-receptors bind at a separate
(invariant) site to the MHC peptide-binding
groove. The specificity of CD4 and CD8 for the
two separate MHC molecules ensures that the
appropriate T cell response is mounted.
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T CELL SIGNALING
CD8
MHC I -PEPTIDE
TCR
T CELL
For T cell signaling to occur, two or more
TCR/co-receptors must be engaged simultaneously.
TCR engagement triggers clustering of the CD3
complex of three protein at the site of peptide
binding.
In addition, the z complex of two proteins is
recruited to the site of peptide binding.
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T CELL SIGNALING
The TCR complex results in an effective division
of labor for TCR signaling
Thus, detection of a bewildering array of ligands
(antigenic peptides) can be converted into a
conserved series of T cell responses.
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T CELL SIGNALING - ADHESION
T cells recognize antigens weakly. For a
productive TCR response, the T cell - APC
interaction must be stabilized by integrins. The
major T cell integrin is LFA-1, which binds
ICAM-1 on APCs.
APC
T CELL
1. LFA-1 is present in a low-affinity binding
state on resting naïve T cells.
2. Exposure to chemokines produced by the innate
immune response converts LFA-1 to a high affinity
state that clusters within minutes.
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T CELL SIGNALING - ADHESION
3. As a result, T cells bind APCs strongly at the
site of infection.
4. Thus, when a TCR encounters an APC presenting
an antigen, the activation of the TCR complex is
strengthened.
APC
T CELL
5. TCR signaling further strengthens the affinity
of LFA-1 for ICAM-1, thereby increasing the
strength of T cell - APC interactions and further
stabilizing T cell signaling.
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T CELL SIGNALING - COSTIMULATORS
Two signals are required to activate a naïve T
cell.
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T CELL RESPONSES - CYTOKINES
T cells respond to antigens and costimulators
with the production of cytokines.
Cytokines are produced mainly by macrophages and
T cells (especially CD4 T cells).
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AND NOW A CONCRETE EXAMPLE IL-2 AND T
CELL CLONAL EXPANSION
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T CELL RESPONSES - CYTOKINES
1. In a resting T cell the IL-2 receptor is in a
low affinity state.
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T CELL RESPONSES - CYTOKINES
1. In the absence of antigenic peptide the number
of antigen-specific T cells is very low.
2. Upon exposure to microbes, APCs present
microbial antigens to antigen-specific T cells.
3. In response to cytokines and stimulation by
APCs, T cell numbers increase rapidly.
4. T cell responses result in a decline in
microbial numbers.
5. Declining microbial numbers result in
declining levels of costimulators and IL-2. As a
consequence T cell numbers also drop.
CELL NUMBER
TIME
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T CELL RESPONSES - CLONAL EXPANSION
The number of T cells specific for any given
antigen is about 1 in every million.
Activation of a given T cell results in clonal
expansion of antigen-specific T cells. During
expansion, only antigen specific T cells expand.
CD8 T cells increase about 10,000-fold and CD4
T cells increase about 100-1,000-fold.
Less CD4 T cells may be required, as their
cytokine production amplifies their effects.
NAÏVE T CELLS
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T CELL RESPONSES - T CELL DIFFERENTIATION
Antigen stimulation activates TCR signaling,
which results in changes in gene expression in T
cells.
The newly induced genes result in the
differentiation of naïve T cells into effector
cells, i.e. cytolytic CD8 T cells and helper
CD4 T cells.
CD8 T cell
CD4 T cell
As CD4 and CD8 T lymphocytes perform distinct
functions their patterns of differentiation are
equally distinct. Differentiation conicides with
clonal expansion and results in the generation of
large numbers of differentiated effector cells.
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T CELL DIFFERENTIATION - CD4 T CELLS
CD4 effector cells produce surface molecules and
cytokines that mainly activate macrophages and B
cells.
Dendritic cells respond by increasing the
expression of costimulators. This results in
further activation of CD4 T cells, which
stimulate further immune responses.
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T CELL DIFFERENTIATION - CD4 T CELLS
CD4 T cells differentiate into various subsets
(types) of helper cells.
The most important cytokine produced by type 1
helper cells is interferon-g (IFN-g).
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T CELL DIFFERENTIATION - CD4 T CELLS
CD4 T cells differentiate into various subsets
(types) of helper cells.
Therefore, Type 2 helper cells stimulate
phagocyte-independent, eosinophil-mediated
immunity, which is particularly effective against
helminths.
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DEVELOPMENT OF MEMORY T CELLS
A fraction of antigen-activated T lymphocytes
persist as memory T cells after an infection has
passed
Memory T cells reside in lymphoid tissues, in
mucosal barriers and in circulation.
Memory T cells do not continue to produce
cytokines or kill infected cells, but they may do
so rapidly upon infection.
Central memory cells populate lymphoid tissues
and are responsible for rapid clonal expansion
after re-exposure to antigen.
Effector memory cells reside in mucoasl tissue
and mediate rapid effector functions after
re-exposure to antigen.
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A PRODUCTIVE T CELL RESPONSE
BARRIERS
SOLUTIONS
1. T cells must encounter the antigen.
APCs concentrate antigens in the lyphoid organs
where naïve T cells circulate.
2. T cells must determine the appropriate
response (CD4 or CD8).
Class I and Class II MHC molecules direct the
specificity of the response.
3. T cells must encounter antigen long enough for
T cell signaling to occur.
Adhesion molecules ensure tight interactions
between T cells and APCs.
4.The T cell response must be directed against
microbial antigens and not harmless proteins.
The requirement for costimulators in T cell
signaling ensures responses are elicited against
microbial antigens.
5. A small number of T cells have to mediate the
initial response.
Several amplification mechanisms (clonal
expansion, cytokine production, etc.) boost the T
cell response to sufficient levels.
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CROSS-TALK BETWEEN INNATE AND ADAPTIVE IMMUNITY
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CROSS-TALK BETWEEN INNATE AND ADAPTIVE IMMUNITY
Adaptive immune responses also influence innate
immune responses.
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SUMMARY

• T lymphocytes mediate cellular immunity against
  intracellular microbes.

2. T cell responses go through phases of
recognition, clonal expansion and differentiation.
3. Accessory molecules are required for T cell
signaling and interactions with APCs.
4. T cells produce cytokines that stimulate T
cell proliferation, or mediate T cell effector
functions.
5. CD4 T cells differentiate into subsets of T
cells.
6. CD8 T cells recognize peptides of
intracellular microbes and may require CD4 help
for differentiation.
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