TCell Maturation,

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Chapter 10 T-Cell Maturation,
Activation, and Differentiation
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• ????
• T-Cell Maturation and the Thymus
• Thymic Selection of the T-Cell Repertoire
• TH-Cell Activation
• T-Cell Differentiation
• Cell Death and T-Cell populations
• Peripheral gd T-Cells

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T-Cell Maturation and the Thymus
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The Human Lymphoid System
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The Normal Rat Thymus
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The Thymus
stromal cells
maturation
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Two-step Selection Process of Thymocytes
Positive Selection permits the survival of
only those T cells whose TCRs recognize
self-MHC molecules. Negative
Selection eliminates T cells that react
too strongly with self-MHC or with self-MHC
plus self-peptides. Thymic stromal cells,
which express high levels of class I and
class II MHC molecules, play a role in this
process.
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• - Any developing thymocytes that are unable to
  recognize
• self-MHC molecules or that do have a high
  affinity for
• self-Ag plus self-MHC (or self-MHC alone) are
  eliminated
• by programmed cell death.
• Thus, only those cells whose receptors
  recognize a self-
• MHC molecules plus foreign Ag are allowed to
  mature.
• - An estimated 95--99 of all thymocyte progeny
  undergo
• programmed cell death within the thymus
  without ever
• maturing.

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• Various features used to characterize the
• pathway of T-cell development in the thymus
• TCR-gene rearrangement
• Activity of genes, such as RAG-1 and RAG-2, that
  are
• involved in TCR rearrangement
• 3. Display of surface Ags specific for T-cell
  differentiation.
• TCR
• CD4
• CD8

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Proposed Pathways for Murine T-cell Development
in the thymus

• Most of the immune thymocytes in the thymus die
• either because they make an unproductive
  TCR-gene
• rearrangement or because they fail positive or
  
• negative selection.
• Mature T-cell populations are produced and move
  to
• the peripheral lymphoid organs.
• Most T cells express the ab TCR and either CD4
  or
• CD8. A few T cells express the gd TCR most of
  these
• lack both CD4 and CD8.

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receptor for stem-cell growth factor
adhesion molecule
IL-2Ra
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Time Course of Appearance of gd Thymocytes and
ab Thymocytes During Mouse Fetal Development
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General Structure of the Pre-TCR and Effects of
Activating it
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• Effects of Signal Transduction
• through the pre-TCR
• - A productive TCR b-chain rearrangement has
  been
• made and selects those thymocytes expressing
  the b
• chain for further expansion and maturation
• Suppresses further rearrangement of TCR b-chain
• genes, resulting in allelic exclusion of the b
  chain
• - Enhances rearrangement of the TCR a chain
• Induces developmental progression to the
  CD4CD8
• double-positive state

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Thymic Selection of the T-Cell Repertoire
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The Thymus Selects for Maturation Only Those T
Cells Whose TCRs Recognize Ag Presented on Target
Cells with the Haplotype of the Thymus
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Positive and Negative Selection of Thymocytes
in the Thymus
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Acquisition of MHC Restriction Depends on
Interaction of Immature Thymocytes with Class I
or Class II MHC Molecules on Epithelial Cells
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CD8 T Cells Only Mature in Transgenics with the
Haplotype (H-2k) Corresponding to the MHC
Restriction of the TCR Transgene
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Negative Selection of Thymocytes Requires Self-Ag
Plus Self-MHC
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TH -Cell Activation
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• Some Common Themes in Signal Transduction
• The involvement of a receptor.
• The generation of second messengers.
• The action of protein kinases and protein
  phosphatases.
• The induced assembly of critical components of a
  signal
• transduction pathway.
• Cascades.
• The involvement of large and small G proteins.
• The default setting for signal transduction
  pathways is
• OFF.

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Initial Steps in TH-Cell Activation
ITAM immunoreceptor tyrosine-based activation
motif
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Overview of Signal Transduction During T-Cell
Activation
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Mechanism of Immunosuppression by Cyclosporin A
(CsA) and FK506
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TH- Cell Activation Requires a Co-stimulatory
Signal Provided by APC
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• Naïve T Cells Require 2 Distinct Signals for
• Activation and Proliferation into Effector Cells
• The initial signal (signal 1) is generated by
  interaction
• of an antigenic peptide with the TCR-CD3
  complex.
• A subsequent Ag-nonspecific co-stimulatory
  signal
• (signal 2) is provided primarily by
  interactions between
• CD28 on the T cell and members of the B7
  family on
• the APC.

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Clonal Expansion versus Clonal Anergy
CD28
no signal 2
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no signal 2
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The Resulting Anergic T Cells Cannot Respond to
Normal APCs
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signal 1
signal 2
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signal 1
signal 2
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Superantigen-mediated Crosslinkage of T-cell
Receptor and Class II MHC Molecules
various bacterial Mls Ags
encoded by mouse exotoxins
mammary tumor virus
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T-Cell Differentiation
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Up-regulation of IL-2 and High-affinity IL-2R
after the Activation of a TH Cell
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TH Cells TH1 subset secretes IL-2, IFN-g, and
TNF-b cell-mediated
functions TH2 subset secretes IL-4, IL-5, IL-6,
and IL-10 helper for B-cell
activation
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T Cell Activation Induced by Different APCs
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Cell Death and T-Cell Populations
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T Cell Death Trigged by Many Different Induction
Pathways
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Fas-induced Cell Death
AICD activation induced cell death
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Peripheral gd T Cells
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• gd T cells
• In humans, gd T cells lt 5
• In mice, gd T cells in lymphoid organs 1 to
  3,
• abundant in the skin and intestinal
  epithelium
• intraepidermal lymphocytes
• - 1 of the epidermal cells in the skin of
  mice are gd T cells.
• - gd TCR-CD3 (), Thy-1 (), CD4 (-), CD8
  (-)
• intestinal intraepithelial lymphocytes
  (iIELs)
• - gd TCR-CD3 (), Thy-1 (), CD8 ()

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• Tissue gd T cells
• - gd T cells in epithelial tissues appear not to
  circulate
• and remain fixed in the tissue sites.
• The gd T cells in different epithelial tissue
  sites
• appear to express different Vg and Vd gene
  segments
• with limited diversity.
• This selective expression of different V gene
• segments in different epithelial tissues may
  reflect a
• specialization of these T cells to respond to
  certain
• types of Ags that tend to be found at these
  sites.

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Ligands Recognized by gd T Cells - Elusive
(?????) - Some gd T cells may bind directly
to a protein Ag without requiring Ag
processing and presentation together with
MHC. Function of gd T Cells - Not clear
- Some gd T cells may be uniquely suited to
respond to heat-shock proteins and may have
evolved to eliminate damaged cells as well
as microbial invaders.
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The End