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Ch.7 The Development of T Lymphocytes Copyright © 2009 by Garland Science Publishing T-cell development in thymus Thymus , T cell and Aging 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 3days 70 years T cell development Thymocyte Development and Differentiation outer cortex DN3 DN2 DN4 TcR beta selection DN1 inner cortex death by neglect inadequate TCR signaling DP MHC Class II recognition positive selection CD4 committed DP cortical epithelial cell MHC Class I recognition negative selection CD8 committed DP lymphoid progenitor hematopoietic precursor medulla periphery periphery adapted from Germain, 2002, Nature Review Immunology Positive selection • Self-MHC-Restriction Epithelial cells in thymus Negative selection • Self-Tolerance Signal Transduction Negative Selection Positive Selection TCR signal Death by Neglect 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