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PD-1/PD-L Blockade Prevents Anergy Induction and Enhances the Anti-Tumor Activities of Glycolipid-Activated Invariant NKT Cells¹

Vrajesh V. Parekh^*, Saif Lalani^*, Sungjune Kim^*, Ramesh Halder, Miyuki Azuma, Hideo Yagita, Vipin Kumar, Lan Wu^* and Luc Van Kaer^2,*

^* Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Invariant NKT (iNKT) cells recognize glycolipid Ags, such as the marine sponge-derived glycosphingolipid -galactosylceramide (GalCer) presented by the CD1d protein. In vivo activation of iNKT cells with GalCer results in robust cytokine production, followed by the acquisition of an anergic phenotype. Here we have investigated mechanisms responsible for the establishment of GalCer-induced iNKT cell anergy. We found that GalCer-activated iNKT cells rapidly up-regulated expression of the inhibitory costimulatory receptor programmed death (PD)-1 at their cell surface, and this increased expression was retained for at least one month. Blockade of the interaction between PD-1 and its ligands, PD-L1 and PD-L2, at the time of GalCer treatment prevented the induction iNKT cell anergy, but was unable to reverse established iNKT cell anergy. Consistently, injection of GalCer into PD-1-deficient mice failed to induce iNKT cell anergy. However, blockade of the PD-1/PD-L pathway failed to prevent bacterial- or sulfatide-induced iNKT cell anergy, suggesting additional mechanisms of iNKT cell tolerance. Finally, we showed that blockade of PD-1/PD-L interactions enhanced the antimetastatic activities of GalCer. Collectively, our findings reveal a critical role for the PD-1/PD-L costimulatory pathway in the GalCer-mediated induction of iNKT cell anergy that can be targeted for the development of immunotherapies.

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 AI070305 (to L.V.K.), HL089667 (to L.V.K.) and CA100660 (to V.K.), a pilot project from the Diabetes Research and Training Center at Vanderbilt (to L.W.), and a postdoctoral fellowship from the National Multiple Sclerosis Society of America (to V.V.P.).

² Address correspondence and reprint requests to Luc Van Kaer, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Medical Center North, Room A-5301, Nashville, TN 37232. E-mail address: luc.van.kaer{at}vanderbilt.edu

³ Abbreviations used in this paper: iNKT, invariant natural killer T; GalCer, -galactosylceramide; DC, dendritic cell; PD, programmed death; PD-L, PD ligand; PerCP, peridinin chlorophyll protein.

⁴ The online version of this article contains supplemental material.

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