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T cell development

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Two fundamental features characterize mature T cell antigen recognition ... Most thymocytes die in thymus - only 2% emerge as mature Tcells ... – PowerPoint PPT presentation

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Title: T cell development


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T cell development
  • Penny Morel
  • 2/29/08
  • 4-0343, morel_at_pitt.edu

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Two 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.

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Two 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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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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Thymocyte developmental stages are defined
by expression of CD4 and CD8 DN DP SP
CD4
CD8
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Successful rearrangement of the beta chain leads
to expression of the pre-TCR on the cell surface.
Nat Rev, Immunol 5571, 2005
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No 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
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Stages of T cell selection and
important signaling molecules
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Signal through pre TCR stimulates
  • Rearrangement of ? chain stops
  • Thymocytes proliferate
  • CD4 and CD8 expression is induced
  • TCR ? gene transcription starts

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Figure 7-21 part 3 of 3
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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)

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Positive 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

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MHC expression is required for ve selection
J. Exp Med. 1861149, 1997
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Cortical 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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Mechanism 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

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CD4 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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Negative 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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Is 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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Diverse tissue antigens are expresssed by
medullary thymic epithelial cells
Gene array analysis
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Medullary Epithelial Cells express antigens from
other tissues - controlled by AIRE (autoimmune
regulator)
Science 2981395, 2002
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AIRE KO mice develop autoimmunity Science
2981395, 2002
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Some T cells interacting with self antigens in
the thymus develop into regulatory T cells
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Figure 13-14
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Role 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

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How 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

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Avidity Hypothesis
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