Ch.7 The Development of T Lymphocytes Copyright © 2009 by Garland Science Publishing

T-cell development in thymus

T cells develop in the thymus The size of thymus is gradually decreased from the birth, and rapidly reduced from puberty Thus, whole T cell repertoire is decreasing with aging Thymus, T cell and Aging 3days70 years

T cell development

DN1 DN2 DN3 DN4 DP lymphoid progenitor cortical epithelial cell MHC Class I recognition MHC Class II recognition death by neglect inadequate TCR signaling outer cortex inner cortex medulla hematopoietic precursor CD8 committed DPCD4 committed DP positive selection negative selection periphery adapted from Germain, 2002, Nature Review Immunology Thymocyte Development and Differentiation TcR beta selection

Positive selection Self-MHC-Restriction Epithelial cells in thymus

Negative selection Self-Tolerance

Signal Transduction Negative Selection TCR signal Death by Neglect Positive Selection About 98% of thymocytes die by apoptosis for their failure in making productive TcR gene rearrangement or failure in receiving survival signal (adequate TcR signal)

T-cell lineage commitment

Notch 4 isotypes in vertebrate: Notch 1~4 Single-pass receptor Ligands: Delta (-like), Serrate (Jagged) Required for early development of thymocytes Intracellular domain of Notch (Notch-IC) delivers the signal

Notch-1 signaling

alpha:beta vs gamma:delta T cells gamma:delta T cells are responsible for about 5% of total peripheral T cells gamma:delta T cells are involved in innate immunity Rearrangement of TcR gamma and delta precedes that of TcR beta

Ig Heavy chain vs TcR beta rearrangement TcR beta chain rearrangement is more efficient for generating productive in-frame chain Why?

CD4 SP: Gata3, ThPOK CD8 SP: Runx1, Runx3

AIRE : autoimmune regulator causes several hundreds of tissue specific genes to be transcribed in the thymic stromal cells