Transcript Chapter 10
Chapter 10 T-cell Maturation, Activation, and Differentiation Dr. Capers 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 Tlineage 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 Click on link to see example http://www.youtube.com/watch?v=tMMrTRnFdI4&f eature=player_detailpage 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 Go onto Next slide Superantigens 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