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Chapter 9 T-cell Development 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 Exit from Thymus and final maturation Mature T cells that survive the selection process leave the thymus ○ Recent thymic emigrants 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