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Dendritic Cells Use Endocytic Pathway for Cross-Priming Class Ib MHC-Restricted CD8⁺TCRβ⁺ T Cells with Regulatory Properties¹

Trevor R. F. Smith^*, Xiaolei Tang^2,*, Igor Maricic^*, Zacarias Garcia, Shaohsuan Fanchiang^* and Vipin Kumar^3,*

^* Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; and Imaging Facility, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

Understanding the mechanisms leading to effective priming of lymphocytes with regulatory properties is crucial for the manipulation of immune responses. CD8⁺TCRβ⁺ T cells are a special subset of innate-like lymphocytes that have been shown to be involved in immune regulation. These cells can recognize self-peptides in the context of a class Ib molecule, Qa-1. How self-Ags are processed in the Qa-1 pathway and presented to CD8⁺TCRβ⁺ T cells is not understood. In this study we demonstrate a cross-presentation pathway by which bone marrow-derived dendritic cells (DCs) capture apoptotic CD4⁺ T cells and process and present TCR-derived peptides in the context of Qa-1 to prime CD8⁺TCRβ⁺ T cells. The priming ability of the DCs is enhanced following TLR signaling using TLR3, TLR4, and TLR9 agonists. DC-mediated cross-presentation is inhibited in the presence of endosomal and proteasomal Ag-processing antagonists. Importantly, DCs loaded with apoptotic T cells prime CD8⁺TCRβ⁺ T cells in vivo, which in turn provides protection from CD4⁺ T cell-mediated autoimmune disease. These data provide a key insight related to processing and presentation of self-Ags in the Qa-1 pathway for priming of CD8⁺TCRβ⁺ T cells and have implications for a DC-based immunotherapeutic approach to inflammatory diseases.

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 Grant R0I AI052227 and by grants from the Multiple Sclerosis National Research Institute and the Diabetes National Research Group (to V.K.).

² Current address: Department of Cancer Immunology and AIDS, Harvard Medical School, Boston, MA 02115.

³ Address correspondence and reprint requests to Dr. Vipin Kumar, Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121. E-mail address: vkumar{at}tpims.org

⁴ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; Ac, acetylated; DC, dendritic cell; ER, endoplasmic reticulum; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; poly(I:C), polyinosinic:polycytidylic acid; PTx, pertussis toxin; Treg, regulatory T cell.