In autoimmune type 1 diabetes, pathogenic T lymphocytes are associated with the specific destruction of insulin-producing β-islet cells. Identification of the autoantigens involved in triggering this process is a central question. Here we examined T cells from pancreatic draining lymph nodes, the site of islet-cell-specific self-antigen presentation. We cloned single T cells in a non-biased manner from pancreatic draining lymph nodes of subjects with type 1 diabetes and from non-diabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from control subjects. The oligoclonally expanded T cells from diabetic subjects with DR4, a susceptibility allele for type 1 diabetes, recognized the insulin A 1-15 epitope restricted by DR4. These results identify insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type 1 diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes.
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Acknowledgements We thank V. Kuchroo and G. Fathman for critical reading of the manuscript. We thank G. Nepom for B cell lines, and R. Neal Smith and N. Kirchhof for expert immunohistochemical and histological tissue staining. These studies were supported by grants to D.A.H. (NIH), to Y.C. (JDRFI Fellowship), to L.B. (NMSS Fellowship) and to S.C.K. (Boston Area Diabetes Endocrinology Research Center). D.A.H. is a recipient of the NIH Javits Investigator Award.
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