Transcript THE T CELL RECEPTOR (TCR)

TODAY
T LYMPHOCYTE DEVELOPMENT
Asilmi 08 - T CELL DEVELOPMENT
THE T CELL RECEPTOR (TCR)
The TCR is a heterodimer
composed of an a and a b
chain.
Each chain contains a
variable (V) and constant
(C) region.
The V and C regions are
similar in structure to the
V and C regions of
Antibodies. Likewise, the
V regions contribute most
to antigen recognition.
In contrast to Antibodies, TCR are anchored in the plasma membrane and
are not secreted.
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The TCR compared with a free Ig molecule.
Both are composed of
two chains that
combine to form
variable and constant
domain.
Both have flexible
hinge regions.
In contrast to an antibody, the TCR is directly and permanently anchored
in the plasma membrane. Thus, the C-terminus has no effector functions,
it is needed for signaling.
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B CELL AND TCR-MEDIATED
ANTIGEN RECOGNITION
1. TCR recognize peptides presented
by MHC molecules. B cell receptor
recognizes antigens without a
requirement for presentation.
2. Recognition is mediated by variable
domains.
3. TCR does not perform effector
functions.
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ANATOMY OF AN MHC-PEPTIDE-TCR COMPLEX
TCR
1. Antigenic peptide contacts the a1 and
a2 domains of the MHC I molecule
Va
Ag
Vb
2. Both the a and b chains of the TCR
interact with the peptide.
a1
a2
b2
a3
3. Additional TCR residues interact with
the MHC molecule.
MHC I
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APC present antigens to T cell on major histocompatibility
complex (MHC) class I and class II molecules.
APC
MHC I
MHC II
APC
CD4
TCR
TCR
CD8
TCR
CD4
CD8
TCR
Tc : CD8
Th : CD4
T Ag are linear molecules in the context of MHC
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THE TCR INTERACTS WITH THE PEPTIDE AND THE MHC
CD4 and CD8 do NOT interact with the
antigenic peptide.
CD4 and CD8 interact with invariant residues
on MHC class II and I.
antigen
Thus, the specificity of the response in not
determined by the identity of the antigen. It is
determined by the nature of the cell presenting
the antigen.
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CD4/CD8 Distinctions fine-tune the adaptive response.
Extracellular microbes: captured and presented on class II by APCs
(macrophages, B cells). CD4 T cells help B cells produce antibodies and
macrophages ingest and destroy. Thus, CD4 T cells activate best
defenses against extracellular microbes.
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CD4/CD8 Distinctions fine-tune the adaptive response.
Intracellular microbes: antigens from cytoplasmic microbes are captured
and presented on class I by all nucleated cells. CD8 T cells directly
eliminate infected cells. Thus, CD8 T cells activate best defenses against
intracellular microbes.
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The end result: a naïve CD4 or CD8 T cell
that recognizes a 3 dimensional surface comprised
of both peptide and MHC.
What a T cell recognizes in an ‘antigen’
is a unique combination of MHC
haplotype and peptide with the
recognition assisted by either CD4 or
CD8.
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FEATURES OF TCR-MEDIATED
ANTIGEN RECOGNITION
1. TCR recognize peptides presented by MHC
molecules.
2. Each clone is specific for a single antigen.
3. Antigen recognition is mediated by specific
domains of the TCR.
4. Signaling triggers T lymphocyte activation.
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TCR proteins on different T cells arise from gene rearrangement
of multiple germ line genes (just like BCR gene rearrangement).
During T cell
development
alpha chain V, J and C
genes recombine to
form the T cell alpha gene
that characterizes
that T cell.
The beta chain gene is
formed from different
V, D, J, and C gene
recombination.
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ALLELIC EXCLUSION
MATERNAL
Va
Ja
Ca
PATERNAL
Va
Ja
Ca
Each individual inherits maternal AND paternal alpha chain genes.
Recombinase rearranges V and J gene segments to form an alpha chain.
If the recombination reaction is productive, recombinase is shut off at the
other alpha chain locus.
Prevents individual cells from expressing more than one TCR.
The same event occurs during BCR rearrangement.
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TCR rearrangement occurs in the thymus.
1
T cell progenitors (thymocytes)
migrate from bone marrow to
the thymus.
2
TCR genes rearrange in the thymus to
produce T cells, which then migrate to
peripheral lymphoid organs to find antigen
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T LYMPHOCYTE MATURATION IN THE THYMUS
6. Negative and positive selection sorts out useful T lymphocytes from
useless, or potentially dangerous T lymphocytes.
THYMIC
EPITHELIAL
CELL
MHC-peptide
TCR
T cells that bind MHC-peptide complexes
survive (positive selection).
TCR
Positive selection ensures that T cells CAPABLE of
interacting with peptide-MHC complexes remain alive.
Positive selection
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T LYMPHOCYTE MATURATION IN THE THYMUS
6. Negative and positive selection sorts out useful T lymphocytes from
useless, or potentially dangerous T lymphocytes.
THYMIC
EPITHELIAL
CELL
MHC-peptide
T cells that bind Class II MHC-peptide complexes
preserve expression of CD4 and lose CD8.
TCR
CD4
CD8
TCR
TCR
CD4
Thus, CD4 T cells develop on the basis of the ability of
their TCR to interact with MHC class II molecules.
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T LYMPHOCYTE MATURATION IN THE THYMUS
6. Negative and positive selection sorts out useful T lymphocytes from
useless, or potentially dangerous T lymphocytes.
THYMIC
EPITHELIAL
CELL
MHC-peptide
TCR
CD8
T cells that bind Class I MHC-peptide complexes
preserve expression of CD8 and lose CD4.
CD4
TCR
TCR
CD8
Thus, CD8 T cells develop on the basis of the ability of
their TCR to interact with MHC class I molecules.
Asilmi 08 - T CELL DEVELOPMENT
T LYMPHOCYTE MATURATION IN THE THYMUS
6. Negative and positive selection sorts out useful T lymphocytes from
useless, or potentially dangerous T lymphocytes.
THYMIC
EPITHELIAL
CELL
T cells that do not recognize MHC molecules
die by apoptosis (failure of positive selection).
MHC-peptide
TCR
CD4
CD8
TCR
This type of selection weeds out useless TCRs that are
INCAPABLE of detecting MHC-antigen complex.
Asilmi 08 - T CELL DEVELOPMENT
T LYMPHOCYTE MATURATION IN THE THYMUS
6. Negative and positive selection sorts out useful T lymphocytes from
useless, or potentially dangerous T lymphocytes.
THYMIC
EPITHELIAL
CELL
T cells that strongly bind MHC-peptide
complexes die by apoptosis (negative
selection).
MHC-peptide
TCR
This type of selection deletes TCRs that detect
self-antigens in complex with MHC molecules
(removes autoreactive lymphocytes).
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thymocyte maturation occurs in stages.
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http://www.ag.uidaho.edu/mmbb/kgustin/mmbb409509/Lectures.html
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Why this complicated system of positive and
negative selection?
1. Positive selection gives MHC restriction but why?
Ensures that CD8+ T cells are specific for complexes of MHC
class I with peptide and that CD4+ T cells are specific for MHC
class II/peptide complexes.
2. Negative selection removes self-reactive cells.
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What happens next?
Is antigen-presentation all that is needed?
The naive CD4 and CD8 T cells
migrate from thymus to peripheral
lymphoid organs to look for antigen
presented on MHC class I or II, then
they clonally expand.
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Two signals are required to activate a naïve T cell.
The second signal comes from the
interaction of APC B7 with T cell
CD28.
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T CELL SIGNALING - COSTIMULATORS
1. “Resting” APCs do not express
costimulators, even though they
may present peptide antigens to T
cells.
2. Naïve T cells that encounter
antigens in the absence of
costimulators become anergic.
3. Microbes or innate immune
cytokines stimulate expression of
costimulators on APCs.
4. Costimulators are recognized by their receptors on T cells and provide
the second signal necessary for T cell activation.
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Not only does 1 signal not activate a naïve T cell,
it makes it anergic (unreactive).
Naïve cell:
1 signal
No killing or
activation
Even if it goes to an APC
that can deliver the second
signal, it cannot be
activated.
Anergy: A state of immune unresponsiveness. Induced when the T cell's
antigen receptor is stimulated in the absence of a second signal.
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Why?
Simultaneous detection of
a foreign antigen and a
second signal activates
the T cell and drives
subsequent immune
responses.
Resting APCs express
little or no co-stimulators
and display self-antigens
that are present in the
tissue.
As a result the T cell becomes anergic and is no longer capable of
mediating immune responses. Thus, anergy serves as an important
safeguard against autoimmunity in the periphery.
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Two signals are required to activate a T cell but only
one for the activated (mature) cell to function.
Naïve CD8 cell:
2 signals:
activated
Activated CD8 cell (CTL):
1 signal
kills.
Asilmi 08 - T CELL DEVELOPMENT