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 T lineage specification

 Progenitor T cells migrate to thymus ○ At about 8 th or 9 th 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

T

reg

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