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¹ Section on Immunology and Immunogenetics, Joslin Diabetes Center; ² Department of Medicine, Brigham and Women's Hospital, ³ Harvard Medical School, Boston, MA 02215

CORRESPONDENCE Diane Mathis OR Christophe Benoist: cbdm{at}joslin.harvard.edu

Foxp3-expressing regulatory T (T reg) cells derive primarily from selection in the thymus. Yet conversion of mature conventional CD4⁺ T (T conv) cell lymphocytes can be achieved in several conditions, such as transforming growth factor ß treatment, homeostatic expansion, or chronic exposure to low-dose antigen. Such conversion might provide a means to generate peripheral tolerance by "converting" potentially damaging T cells that react to self-antigens. We tested this hypothesis in mice transgenic for the BDC2.5 T cell receptor (TCR), which is representative of a diabetogenic specificity that is naturally present in NOD mice and reactive against a pancreatic self-antigen. In the thymus, before any exposure to antigen, clonotype-positive T reg and T conv cells express a second TCR chain derived from endogenous loci. High-throughput single-cell sequencing of secondary TCRs of the V2 family showed their joining CDR3 regions to be very different in T reg and T conv cell thymocytes. These specific CDR3 motifs, thus, provided a "tag" with which to test the actual impact of T conv to T reg cell conversion in response to peripheral self-antigen; should the autoreactive clonotypic TCR induce T conv to T reg cell conversion upon encounter of cognate antigen in the pancreas or draining lymph node, one would expect to detect tag CDR3 motifs from T conv cells in the T reg cell populations. Sequencing large numbers of peripheral BDC⁺V2⁺ cells showed that little to no conversion occurs in response to this pancreatic autoantigen.

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