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Abstract
Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Here we show, by analyzing >2 × 108TCRB sequences of circulating naive, central memory, regulatory and stem cell-like memory CD4+ T cell subsets from patients with type 1 diabetes and healthy donors, that patients have shorter TCRB complementarity-determining region 3s (CDR3), in all cell subsets, introduced by increased deletions/reduced insertions during VDJ rearrangement. High frequency of short CDR3s is also observed in unproductive TCRB sequences, which are not subjected to thymic culling, suggesting that the shorter CDR3s arise independently of positive/negative selection. Moreover, TCRB CDR3 clonotypes expressed by autoantigen-specific CD4+ T cells are shorter compared with anti-viral T cells, and with those from healthy donors. Thus, early events in thymic T cell development and repertoire generation are abnormal in type 1 diabetes, which suggest that short CDR3s increase the potential for self-recognition, conferring heightened risk of autoimmune disease.
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1 Department of Immunobiology, Faculty of Life Sciences & Medicine, King’s College London, 2nd Floor, Borough Wing, Guy’s Hospital, London, UK; National Institute for Health Research, Biomedical Research Centre at Guy’s and St Thomas’ Hospital Foundation Trust and King’s College London, Guy’s Hospital, London, UK; Immunology Laboratory, Biomedical Research Center (CINBIO), Centro Singular de Investigación de Galicia, University of Vigo, Campus Universitario de Vigo, Pontevedra, Spain
2 Department of Immunobiology, Faculty of Life Sciences & Medicine, King’s College London, 2nd Floor, Borough Wing, Guy’s Hospital, London, UK
3 Department of Immunobiology, Faculty of Life Sciences & Medicine, King’s College London, 2nd Floor, Borough Wing, Guy’s Hospital, London, UK; National Institute for Health Research, Biomedical Research Centre at Guy’s and St Thomas’ Hospital Foundation Trust and King’s College London, Guy’s Hospital, London, UK