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Cutting Edge: In Vivo Trogocytosis as a Mechanism of Double Negative Regulatory T Cell-Mediated Antigen-Specific Suppression¹

Megan S. Ford McIntyre^2,*,, Kevin J. Young^2,*,, Julia Gao^*,, Betty Joe^* and Li Zhang^3,*,,

^* Multi-Organ Transplantation Program, Toronto General Research Institute, University Health Network, Department of Laboratory Medicine and Pathobiology, and Department of Immunology, University of Toronto, Toronto, Canada

Recent data have demonstrated that treatment with β-TCR⁺CD3⁺CD4^–CD8^–NK1.1^– double negative (DN) regulatory T cells (Tregs) inhibits autoimmune diabetes and enhances allotransplant and xenotransplant survival in an Ag-specific fashion. However, the mechanisms whereby DN Tregs suppress Ag-specific immune responses remain largely unknown. In this study, we demonstrate that murine DN Tregs acquire alloantigen in vivo via trogocytosis and express it on their cell surface. Trogocytosis requires specific interaction of MHC-peptide on APCs and Ag-specific TCR on DN Tregs, as blocking this interaction prevents DN Treg-mediated trogocytosis. Acquisition of alloantigen by DN Tregs was required for their ability to kill syngeneic CD8⁺ T cells. Importantly, DN Tregs that had acquired alloantigen were cytotoxic toward Ag-specific, but not Ag-nonspecific, syngeneic CD8⁺ T cells. These data provide new insight into how Tregs mediate Ag-specific T cell suppression and may enhance our ability to use DN Tregs as a therapy for transplant rejection and autoimmune 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 the Canadian Institute of Health Research and the Canadian Cancer Society.

² M.S.F. and K.J.Y. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Li Zhang, Toronto General Hospital Research Institute, Toronto Medical Discovery Tower 2-807, 101 College Street, Toronto, Ontario, Canada M5G 1L7. E-mail address: lzhang{at}uhnres.utoronto.ca

⁴ Abbreviations used in this paper: Treg, regulatory T cell; 7-AAD, 7-aminoactinomyin D; DN, double negative; MCMV, mouse CMV.

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