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Antigen Specificity Acquisition of Adoptive CD4⁺ Regulatory T Cells via Acquired Peptide-MHC Class I Complexes¹

Siguo Hao^*, Jinying Yuan^*, Shulin Xu^*, Manjunatha Ankathatti Munegowda^*, Yulin Deng^*, John Gordon, Zhou Xing and Jim Xiang^2,*

^* Departments of Oncology, Microbiology, and Immunology, Research Unit, Saskatchewan Cancer Agency, College of Medicine, Department of Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

The Ag-specific CD4⁺ regulatory T (Tr) cells play an important role in immune suppression in autoimmune diseases and antitumor immunity. However, the molecular mechanism for Ag-specificity acquisition of adoptive CD4⁺ Tr cells is unclear. In this study, we generated IL-10- and IFN--expressing type 1 CD4⁺ Tr (Tr1) cells by stimulation of transgenic OT II mouse-derived naive CD4⁺ T cells with IL-10-expressing adenovirus (AdV_IL-10)-transfected and OVA-pulsed dendritic cells (DC_OVA/IL-10). We demonstrated that both in vitro and in vivo DC_OVA/IL-10-stimulated CD4⁺ Tr1 cells acquired OVA peptide MHC class (pMHC) I which targets CD4⁺ Tr1 cells suppressive effect via an IL-10-mediated mechanism onto CD8⁺ T cells, leading to an enhanced suppression of DC_OVA-induced CD8⁺ T cell responses and antitumor immunity against OVA-expressing murine B16 melanoma cells by 700% relative to analogous CD4⁺ Tr1 cells without acquired pMHC I. Interestingly, the nonspecific CD4⁺25⁺ Tr cells can also become OVA Ag specific and more immunosuppressive in inhibition of OVA-specific CD8⁺ T cell responses and antitumor immunity after uptake of DC_OVA-released exosomal pMHC I complexes. Taken together, the Ag-specificity acquisition of CD4⁺ Tr cells via acquiring DC’s pMHC I may be an important mean in augmenting CD4⁺ Tr cell suppression.

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 study was supported by a research grant (MOP 79415) from the Canadian Institutes for Health Research. S.H. was supported by a Postdoctoral Fellowship from the Saskatchewan Health Research Foundation.

² Address correspondence and reprint requests to Dr. Jim Xiang, Saskatoon Cancer Center, 20 Campus Drive, Saskatoon, Saskatchewan S7N 4H4, Canada. E-mail address: jim.xiang{at}saskcancer.ca

³ Abbreviations used in this paper: Tr, regulatory T; DC, dendritic cell; pMHC I, peptide MHC class I; AdV, adenovirus; GITR, glucocorticoid-induced TNFR; KO, knockout; BM, bone marrow; EXO/exo, exosome.