Chapter 10 T-cell Maturation, Activation, and Differentiation Dr. Capers Immunology

Kindt • Goldsby • Osborne Kuby IMMUNOLOGY Sixth Edition Chapter 10 T-Cell Maturation, Activation, and Differentiation Copyright © 2007 by W. H. Freeman and Company

Progenitor T cells migrate from bone marrow to thymus T cells can be grown in vitro in absence of thymic fragments Grown on bone marrow stem cells with Notch protein Notch protein is key in determining T-lineage specification

Progenitor T cells migrate to thymus At about 8th or 9th week of gestation in humans T cell maturation involves rearrangements of the germ-line TCR genes In thymus, thymocytes proliferate and differentiate

Selection process in thymus Positive selection Survival of only T cells whose TCRs recognize self-MHC molecules Negative selection Eliminates T cells that react too strongly with self MHC or MHC with self-peptides

T-cell Development Begins with arrival of small numbers of lymphoid precursors migrating from blood to thymus When they do arrive in thymus, T-cell precursors don’t express signature surface markers (CD3, CD4, and CD8) Do not express RAG-1 or RAG-2 that are necessary for gene rearrangement

T-cell Development During 3 week development, differentiating T cells pass through stages of development based on surface phenotypes

DN = Double negative CD4- and CD8- DP = Double positive CD4+ and CD8+ C-kit – receptor for stem cell growth factor CD44 – an adhesion molecule CD25 - alpha chain of IL-2 receptor

T cell development is expensive for host 98% of all thymocytes do not mature, die by apoptosis within thymus

Insertion of rearranged TCR genes suppress other gene rearrangements in these mice

T cell Activation Initiated by TCR-CD3 complex with processed antigen on MHC molecule CD8+ cells with Class I CD4+ cells with Class II Initiates cascade of biochemical events Inducing resting T cell to enter cell cycle, proliferate, differentiate into memory and effector T cells

T cell Activation Cascade of biochemical events leading to gene expression: Interaction of signal and molecule (example: TCR + MHC and antigen) Generation of “second messenger” that diffuses to other areas of cell Protein kinases and protein phosphatases are activated or inhibitied Signals are amplified by enzyme cascades http://www.youtube.com/watch?v=tMMrTRnFdI4&feature=player_detailpage Click on link to see example

T cell Activation Gene products after activation Immediate genes (1/2 hour of recognition) Transcription factors (c-Myc, NFAT, NF-κB) Early genes (1-2 hours from recognition) IL-2, IL2R, IL-6, IFN-γ Late genes (more than 2 days later) Encode adhesion molecules

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Superantigens Exogeneous Endogeneous Bind to BOTH the TCR and MHC Can cause over-activation Overproduction of TH-cell cytokines, leading to systemic toxicity Exogeneous Variety of exotoxins secreted by some Gram+ bacteria Endogeneous Cell membrane proteins encoded by viruses

T-Cell Differentiation CD4+ and CD8+ cells leave thymus and enter circulation in G0 phase Naïve cells (condensed chromatin, little cytoplasm) About twice as many CD4+ Naïve cell recognized MHC-antigen complex Initiated primary response After 48 hours, enlarges into blast cell and undergoes repeated rounds of cell division Differentiate into: Effector cells – cytokine secretion, B-cell help Memory cells – long lived, respond with heightened activity (secondary response)

Treg Cells Shown to inhibit proliferation of other T cells in vitro CD4+CD25+ Shown to inhibit development of autoimmune diseases

Cell Death and T Cell Populations Apoptosis plays critical role Deletion of potentially autoreactive thymocytes Deletion of T cell populations after activation Fas and FasL pathway to induce self death