Title: T cell development
1 T cell development
- Penny Morel
- 2/29/08
- 4-0343, morel_at_pitt.edu
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3Two fundamental features characterize mature T
cell antigen recognition
- MHC restriction T cells recognize foreign
peptides bound in the groove of self MHC class I
or class II molecules. - Self tolerance T cells cannot recognize self
peptides bound in the groove of self MHC class I
or class II molecules.
4Two critical requirements for mature T cell
development
- T cell antigen receptor (TCR) Without
rearrangement and expression of a functional TCR
no T cells will develop. e.g. SCID - Thymus The thymus is the organ in which TCR
rearrangement and selection takes place. In
DiGeorge syndrome the thymus fails to develop and
the individual can produce B cells but no T cells
develop.
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6 Thymus
- Located in mediastinum
- Has cortex and medulla Cortex from third
branchial cleft of the ectoderm medulla from
third pharyngeal pouch of the endoderm - T cell precursors enter thymus from BM -
Thymocytes. - Most thymocytes die in thymus - only 2 emerge as
mature Tcells
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8Thymocyte developmental stages are defined
by expression of CD4 and CD8 DN DP SP
CD4
CD8
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14Successful rearrangement of the beta chain leads
to expression of the pre-TCR on the cell surface.
Nat Rev, Immunol 5571, 2005
15No ligand has been identified for the pre-TCR,
But this paper shows that when TCR ? and pre T?
are expressed they localize to the lipid raft and
initiate signaling. SCIET - Scid-derived
thymocyte cell line SCB.29 - with transfected TCR
? chain MCD - disrupts rafts PP2 - inhibits lck
phosphorylation
Nature 406524, 2000
16Stages of T cell selection and
important signaling molecules
17Signal through pre TCR stimulates
- Rearrangement of ? chain stops
- Thymocytes proliferate
- CD4 and CD8 expression is induced
- TCR ? gene transcription starts
18Figure 7-21 part 3 of 3
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20 Features of TCR rearrangement
- V-D-J (b) and V-J (a,g,d) rearrangements
- N region diversity (N, P)
- D regions can be read in all three frames
- Successive rearrangements are possible
- 1016 potential ab TCR, 1018 gd TCR
- No somatic mutation
- No allelic exclusion at TCRa locus (30 of T
cells have 2 a rearrangements 5-10 T cells in
periphery express 2 TCR)
21Positive Selection of ab TCR
- TCR rearrangement is a random process - many TCR
generated that cannot recognize self MHC - TCR rearrangement signals expression of CD4 and
CD8 -double positive thymocytes - Cells expressing TCR interact with thymic
epithelial cells of the cortex - these cells
express high levels of self MHC class I and class
II molecules that contain peptides
22MHC expression is required for ve selection
J. Exp Med. 1861149, 1997
23Cortical thymic epithelium mediates positive
selection
- Bone marrow chimeric experiments
- Animals are irradiated with high doses of
radiation - kills the bone marrow, but the thymic
epithelium is radioresistant. - The immune system is reconstituted by the
injection of bone marrow from healthy animal
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26Mechanism of positive selection
- If TCR, CD4, CD8 thymocytes do not bind to MHC
expressed on thymic epithelium they will die - Positive selection is a rescue from death
- 50 x 106 thymocytes die each day because they
fail positive selection
27CD4 and CD8 expression
- Choice of which coreceptor to express is part of
positive selection - Instructive model CD4 interacts with MHC class
II, delivers signal to T cell, CD8 expression is
turned off - Stochastic/selection model double positive
thymocytes randomly decrease expression of CD4 or
CD8 and only those cells with coreceptor
appropriate for their TCR will survive
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29Negative Selection
- Occurs at cortico medullary junction
- Occurs by clonal deletion
- Cells express high levels of TCR and have
downregulated either CD4 or CD8 - Interact with bone marrow-derived APC (dendritic
cells or macrophages) that present self antigens
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31Is negative selection effective?
- Yes - if protein is highly expressed in thymus
- Transcription factor called autoimmune regulator
(AIRE) turns on expression of self proteins such
as insulin in the thymus - Mutations in AIRE are the cause of
APS1(autoimmune polyendocrinopathy syndrome type
1) - a rare autoimmune disease
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33Diverse tissue antigens are expresssed by
medullary thymic epithelial cells
Gene array analysis
34Medullary Epithelial Cells express antigens from
other tissues - controlled by AIRE (autoimmune
regulator)
Science 2981395, 2002
35AIRE KO mice develop autoimmunity Science
2981395, 2002
36Some T cells interacting with self antigens in
the thymus develop into regulatory T cells
37Figure 13-14
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39Role of TSLP in Treg development
- Thymic stromal lymphopoetin (TSLP) expressed in
Hassalls corpuscles of thymus - Nature 4361181,
2005 - TSLP induces DC maturation
- TSLP-induced DC stimulates the production of
CD25 Tregs
40How does the same interaction induce both
positive and negative selection?
- Avidity Hypothesis - threshold binding for MHC by
the TCR required to signal positive selection is
lower than the threshold required for negative
selection - Differential signaling hypothesis - nature of
signal delivered by TCR differs antagonist vs
agonist peptides
41Avidity Hypothesis
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