TODAY

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TODAY
T LYMPHOCYTE DEVELOPMENT Chapter 4. Pages 63 -
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REMINDER WE DISTINGUISH TWO GENERAL CLASSES OF T
LYMPHOCYTES
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THE T CELL RECEPTOR (TCR)
The V and C regions are similar in structure to
the V and C regions of Antibodies. Likewise, the
V regions contains three hypervariable regions,
of which CDR3 contributes 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.
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B CELL AND TCR-MEDIATED ANTIGEN RECOGNITION
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ANATOMY OF AN MHC-PEPTIDE-TCR COMPLEX
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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 determine the type of T cell that
responds.
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Why do CD4 T cells interact MHC II and CD8 T
cells with MHC I?
Enhanced complex stability increases the strength
of TCR signaling.
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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
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TCR proteins on different T cells arise from gene
rearrangement of multiple germ line genes (just
like BCR gene rearrangement).
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ALLELIC EXCLUSION
PATERNAL
MATERNAL
Va
Ca
Ja
Va
Ca
Ja
Each individual inherits maternal AND paternal
alpha chain genes.
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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Summary of theoretical diversity of BCR and TCR
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TCR rearrangement occurs in the thymus.
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T LYMPHOCYTE MATURATION
3. V-D-J recombination is initiated at the beta
chain locus.
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T LYMPHOCYTE MATURATION
4. Signals generated by the pre-TCR promote T
lymphocyte survival, proliferation allelic
exclusion at the beta chain locus and TCR alpha
chain recombination.
Pre-TCR
PRE-T CELL
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T LYMPHOCYTE MATURATION
6. Negative and positive selection processes then
sort out useful T lymphocytes from useless, or
potentially dangerous T lymphocytes.
T cells that do not recognize MHC molecules die
by apoptosis.
T cells that strongly bind MHC-peptide complexes
die by apoptosis (negative selection).
T cells that bind MHC-peptide complexes survive
(positive selection).
T cells that bind Class I MHC-peptide complexes
preserve expression of CD8 and lose CD4.
T cells that bind Class II MHC-peptide complexes
preserve expression of CD4 and lose CD8.
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The thymocytes maturation occurs in stages.
http//www.ag.uidaho.edu/mmbb/kgustin/mmbb409509/L
ectures.html
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Why this complicated system of positive and
negative selection?

• Positive selection gives MHC restriction but why?

Ensures that T cells are MHC-restricted.
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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How do the higher affinity binding cells survive?
By producing growth and survival factors that act
only at short range. Thus, the cells bound
survive those not die by apoptosis
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What happens to the T lymphocytes after the
thymus?
The CD4 and CD8 positive T cells leave the thymus
and go to lymph nodes or spleen. They leave the
thymus unactivated they are in the G0 stage of
the cell cycle.
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What happens next?
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.
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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.
This is another way of preventing self reaction
(autoimmunity)
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Why?
What if a self peptide is expressed and the
corresponding T cells expressing TCRs are not
eliminated in the thymus? This mechanism
provides a backup the T cell expressing a self
reactive TCR would be stunned when it encounters
the peptide on MHC class I outside the thymus and
not expand.
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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.
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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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