The autoimmune condition is a primary obstacle to inducing tolerance in type 1 diabetes patients receiving allogeneic pancreas transplants. It is unknown how autoreactive T cells that recognize self-MHC molecules contribute to MHC-disparate allograft rejection. In this report, we show the presence and accumulation of dual-reactive, that is autoreactive and alloreactive, T cells in C3H islet allografts that were transplanted into autoimmune diabetic NOD mice. Using high-throughput sequencing, we discovered that T cells prevalent in allografts share identical TCRs with autoreactive T cells present in pancreatic islets. T cells expressing TCRs that are enriched in allograft lesions recognized C3H MHC molecules, and five of six cell lines expressing these TCRs were also reactive to NOD islet cells. These results reveal the presence of autoreactive T cells that mediate cross-reactive alloreactivity, and indicate a requirement for regulating such dual-reactive T cells in tissue replacement therapies given to autoimmune individuals. The Journal of Immunology, 2018, 200: 1504–1512.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institute of Diabetes and Digestive Kidney Diseases (Grants DK080885, DK099317, DK099187, DK032083, DK104223, and DK110845), the Juvenile Diabetes Research Foundation (Grant 1-INO-2014-173-A-V), the Children’s Diabetes Foundation, the Peter Cul-shaw Family Award, the Children’s Hospital Colorado Research Institute (Grant CHC G0100529), and the Colorado Clinical and Translational Science Institute (Grant TR001082). A.L.B. is supported by University of Minnesota T32 fellowship in Endocrinology (Grant T32DK007203-38).
Copyright © 2018 by The American Association of Immunologists, Inc.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't