The Journal of Experimental Medicine
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Published online 20 November 2006 doi:10.1084/jem.20061577
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 12, 2737-2747
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ARTICLE

 Insulin-induced remission in new-onset NOD mice is maintained by the PD-1–PD-L1 pathway

Brian T. Fife1, Indira Guleria2, Melanie Gubbels Bupp1, Todd N. Eagar1, Qizhi Tang1, Helene Bour-Jordan1, Hideo Yagita3, Miyuki Azuma4, Mohamed H. Sayegh2, and Jeffrey A. Bluestone1

1 UCSF Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143
2 Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Boston, MA 02115
3 Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
4 Department of Molecular Immunology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan

CORRESPONDENCE Jeffrey A. Bluestone: jbluest{at}diabetes.ucsf.edu.

The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)–programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte–associated antigen 4 pathway. Anti–PD-1 and anti–PD-L1, but not anti–PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1–PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1–PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1–PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.

Abbreviations used: antigen-SP, antigen-coupled splenocyte(s); CTLA-4, cytotoxic T lymphocyte–associated antigen 4; EAE, experimental autoimmune encephalitis; ECDI, ethylene carbodiimide; INS-SP, insulin-coupled fixed splenocyte(s); NOD, nonobese diabetic; p31-SP, 1040-p31 peptide–coupled ECDI-fixed splenocyte(s); PD-1, programmed death 1; PD-L, programmed death ligand; pLN, pancreatic LN; SHAM-SP, irrelevant peptide–coupled ECDI-fixed splenocyte(s); T1D, type 1 diabetes; T eff, effector T; Tg, transgenic; T reg, T regulatory.

M. Gubbels Bupp's present address is Roche Pharmaceuticals, Palo Alto, CA 94304.


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