In autoimmune type 1 diabetes, pathogenic T lymphocytes are associated with the specific destruction of insulin-producing β-islet cells1,2. 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 presentation3. 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 diabetes4, 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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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.
The authors declare that they have no competing financial interests.
Histological examination of pancreas and lymphocytic infiltrate in islets from diabetic subject 3. (PDF 896 kb)
Histological examination of pancreas from a long term diabetes subject (2). (PDF 1277 kb)
Supplementary Table S1: oligoclonal Vβ Chain Usage of T-cell clones isolated from subjects with Type 1 diabetes. Supplementary Table S2: oligoclonal Vα Sequences of T-cell clones expressing identical Vβ chains from diabetic pancreatic draining lymph nodes. Supplementary Table S3: TCR Vβ from PLN-derived insulin-reactive Ba.14 T-cell clone is not detected in diabetic subject 2 (Ba) spleen. (PDF 118 kb)
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Kent, S., Chen, Y., Bregoli, L. et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435, 224–228 (2005). https://doi.org/10.1038/nature03625
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