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The Journal of Immunology, 2006, 177: 8291-8295.
Copyright © 2006 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Programed Death (PD) Ligand-1/PD-1 Interaction Is Required for CD8+ T Cell Tolerance to Tissue Antigens1

Natalia Martin-Orozco*, Yi-Hong Wang*, Hideo Yagita{dagger} and Chen Dong2,*

* M. D. Anderson Cancer Center, Houston, TX 77030; and {dagger} Juntendo University School of Medicine, Tokyo, Japan

Constitutive presentation of tissue Ags by dendritic cells results in tolerance of autoreactive CD8+ T cells; however, the underlying molecular mechanisms are not well understood. In this study we show that programmed death (PD)-1, an inhibitory receptor of the CD28 family, is required for tolerance induction of autoreactive CD8+ T cells. An antagonistic Ab against PD-1 provoked destructive autoimmune diabetes in RIP-mOVA mice expressing chicken OVA in the pancreatic islet cells, which received naive OVA-specific CD8+ OT-I cells. This effect was mediated by the PD ligand (PD-L) PD-L1 but not by PD-L2. An increased number of effector OT-I cells recovered from the pancreatic lymph nodes of anti-PD-L1-treated mice showed down-regulation of PD-1. Furthermore, the blockade of PD-1/PD-L1 interaction during the priming phase did not significantly affect OT-I cell division but enhanced its granzyme B, IFN-{gamma}, and IL-2 production. Thus, during the presentation of tissue Ags to CD8+ T cells, PD-1/PD-L1 interaction crucially controls the effector differentiation of autoreactive T cells to maintain self-tolerance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work is supported in part by grants from the National Institutes of Health (to C.D.). C.D. is a Cancer Research Institute Investigator and a Trust Fellow of the M. D. Anderson Cancer Center.

2 Address correspondence and reprint requests to Dr. Chen Dong, Department of Immunology, M. D. Anderson Cancer Center, 7455 Fannin, Unit 906, Houston, TX 77030. E-mail address: cdong{at}mdanderson.org

3 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; mOVA, membrane-bound chicken OVA; PD, programmed death; PD-L, PD ligand; PLN, pancreatic LN; RIP, rat insulin promoter.




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