Mechanisms of PDL1-mediated regulation of autoimmune diabetes

Indira Guleria, Melanie Gubbels Bupp, Shirine Dada, Brian Fife, Qizhi Tang, Mohammed Javeed Ansari, Subbulaxmi Trikudanathan, Nidyanandh Vadivel, Paolo Fiorina, Hideo Yagita, Miyuki Azuma, Mark Atkinson, Jeffrey A. Bluestone, Mohamed H. Sayegh

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

The PD-1-PDL1 pathway plays a critical role in regulating autoimmune diabetes as blockade or deficiency of PD-1 or PDL1 results in accelerated disease in NOD mice. We explored the cellular mechanisms involved in the regulation of these autoimmune responses by investigations involving various gene-deficient mice on the NOD background. Administration of blocking anti-PDL1 antibody to CD4+ T cell-deficient, CD8+ T cell-deficient and B cell-deficient mice demonstrated that PDL1-mediated regulation of autoreactive CD4+ and CD8+ T cells is critical for diabetes development. This concept was confirmed by adoptive transfer studies utilizing lymphocytes from BDC2.5 and 4.1 (CD4+) TCR transgenic mice and 8.3 (CD8+) TCR transgenic mice; efforts showing increased proliferation of both CD4+ and CD8+ T cells following PDL1 blockade in vivo. Furthermore, we observed that anti-PDL1-mediated acceleration is dependent upon events occurring in the pancreatic lymph nodes during early disease stages, but becomes independent of the pancreatic lymph nodes during later disease stages. These data provide strong evidence that PDL1 regulates autoimmune diabetes by limiting the expansion of CD4+ and CD8+ autoreactive T cells, and define the timing and locale of PDL1-mediated regulation of type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)16-25
Number of pages10
JournalClinical Immunology
Volume125
Issue number1
DOIs
StatePublished - Oct 2007

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants P01-AI56299, P01-AI041521 and Juvenile Diabetes Research Foundation Center Grant on Immunological Tolerance in type 1 diabetes (to M.H. Sayegh), National Institutes of Health grant P01 AI-42288 (to M. Atkinson) and JDRF Islet Transplant Center # 4-2004-372 and U19 AI056388 grants (to J.A. Bluestone).

Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.

Keywords

  • NOD
  • Negative costimulatory pathways
  • Programmed death ligand
  • Type 1 diabetes

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