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PD-1 Regulates Self-Reactive CD8⁺ T Cell Responses to Antigen in Lymph Nodes and Tissues¹

Mary E. Keir^*, Gordon J. Freeman and Arlene H. Sharpe^2,*

^* Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, and Department of Medical Oncology, Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115

PD-1, an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. We tested the role of PD-1:PD-1 ligand (PD-L) interactions in cross-presentation and the generation and control of CD8⁺ responses against self-Ag. Ag-naive PD-1^–/– OVA-specific OT-I CD8⁺ T cells exhibited exacerbated responses to cross-presented Ag in mice expressing soluble OVA under the control of the rat insulin promoter (RIP-ova^high). Following adoptive transfer into RIP-ova^high recipients, PD-1^–/– OT-I T cells expanded in the pancreatic lymph node. In contrast to wild-type OT-I cells, PD-1^–/– OT-I T cells secreted IFN- and migrated into the pancreas, ultimately causing diabetes. Loss of PD-1 affected CD8⁺ cells intrinsically, and did not significantly alter the responses of wild-type OT-I T cells adoptively transferred into the same RIP-ova^high recipient mouse. PD-1:PD-L interactions also limited CD8⁺ effector cells, and PD-L1 expression on parenchymal tissues protected against effector OT-I T cell attack. Finally, we found that the loss of PD-1 on effector OT-I cells lowers the threshold for Ag recognition in peripheral tissues. These findings indicate two checkpoints where PD-1 attenuates self-reactive T cell responses: presentation of self-Ag to naive self-reactive T cells by dendritic cells in the draining lymph node and reactivation of pathogenic self-reactive T cells in the target organ.

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 was supported by National Institutes of Health Grants AI40614 and AI39671; the National Multiple Sclerosis Society (to A.H.S.); NIH Grant AI056299 (to A.H.S. and G.J.F.); and a Cancer Research Institute fellowship (to M.E.K.).

² Address correspondence and reprint requests to Dr. Arlene H. Sharpe, Immunology Research Division, Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115. E-mail address: arlene_sharpe{at}hms harvard.edu

³ Abbreviations used in this paper: DC, dendritic cell; ES, embryonic stem; ILN, inguinal lymph node; PD-1, programmed cell death-1; PD-L, programmed cell death ligand; PLN, pancreatic lymph node; RIP, rat insulin promoter; WT, wild type.