Chapter 9 T-cell Development Immunology

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

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