A discrete T cell receptor repertoire is censored at wave 1 of thymic selection — ASN Events

A discrete T cell receptor repertoire is censored at wave 1 of thymic selection (#19)

Rushika C Wirasinha 1 2 , Manu Singh 3 , Stuart Archer 4 , Jin Yan Yap 5 , Anna Chan 1 2 , Paul Harrison 4 , Chris Goodnow 3 6 , Stephen Daley 1 2
  1. Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  3. Immunology Division, Garvan Institute, Darlinghurst, Sydney, Australia
  4. Monash Bioinformatics Platform, Monash University, Clayton, VIC, Australia
  5. Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
  6. St. Vincent's Clinical School, University of New South Wales, Sydney, Australia

Self-reactive thymocytes that bind strongly to a self-antigen in the thymic cortex are prevented from becoming naïve conventional T cells (T-conv) by a number of mechanisms. Many self-reactive thymocytes are deleted by apoptosis, whereas agonist selection in the thymic cortex diverts other self-reactive thymocytes into the intestinal CD8αα+ intraepithelial lymphocyte (IEL) lineage. Two thymocyte-intrinsic mechanisms have been proposed to explain how self-reactive thymocytes commit to the IEL lineage: TCR signals received by IEL precursors (IELp) are thought to be either earlier or stronger than TCR signals received by T-conv precursors, the CD4+ and CD8+ single positive (SP) thymocytes. To distinguish between these hypotheses, we purified thymocyte subsets from mice with a fixed TCRβ chain and deep-sequenced TCRα chain transcripts. We found that the IELp TCRα chain repertoire was at least as diverse as, and clearly distinct from, the CD4SP and CD8SP T-conv repertoires. Based on the chromosomal position of TRAJ gene segments used, the results indicate that early TCR signals are neither necessary nor sufficient for IELp commitment. However, IELp were frequently misdirected into the T-conv lineage in mice with attenuated TCR signaling due to mutations in Zap70. Our data demonstrate that strong TCR signals via Zap70 divert cortical thymocytes into the IEL lineage, thereby preventing a large burden of self-reactive thymocytes from becoming naïve conventional T cells.

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