The programmed Death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo

Alison M. Paterson, Keturah E. Brown, Mary E. Keir, Vijay K. Vanguri, Leonardo V. Riella, Anil Chandraker, Mohamed H. Sayegh, Bruce R. Blazar, Gordon J. Freeman, Arlene H. Sharpe

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1: B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4+ and CD8+ T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4+ and CD8+ T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis. Copyright

Original languageEnglish (US)
Pages (from-to)1097-1105
Number of pages9
JournalJournal of Immunology
Volume187
Issue number3
DOIs
StatePublished - Aug 1 2011

Fingerprint Dive into the research topics of 'The programmed Death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo'. Together they form a unique fingerprint.

  • Cite this

    Paterson, A. M., Brown, K. E., Keir, M. E., Vanguri, V. K., Riella, L. V., Chandraker, A., Sayegh, M. H., Blazar, B. R., Freeman, G. J., & Sharpe, A. H. (2011). The programmed Death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. Journal of Immunology, 187(3), 1097-1105. https://doi.org/10.4049/jimmunol.1003496