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Regulatory T Cell Suppression Is Potentiated by Target T Cells in a Cell Contact, IL-35- and IL-10-Dependent Manner¹

Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

Regulatory T cells (T_reg) are believed to suppress conventional T cell (T_conv) proliferation in vitro in a contact-dependent, cytokine-independent manner, based in part on experiments in which T_reg and T_conv are separated by a permeable membrane. We show that the production of IL-35, a novel inhibitory cytokine expressed by natural T_reg, increases substantially following contact with T_conv. Surprisingly, T_reg were able to mediate potent suppression of T_conv across a permeable membrane when placed in direct contact with T_conv in the upper chamber of a Transwell plate. Suppression was IL-35 and IL-10 dependent, and T_conv activation was required for maximal potentiation of T_reg suppression. These data suggest that it is the induction of suppression, rather than the function of T_reg that is obligatorily contact dependent.

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 R01 AI39480, National Cancer Institute Comprehensive Cancer Center Support Center of Research Excellence Grant CA21765, the American Lebanese Syrian Associated Charities (to D.A.A.V.), a St. Jude Gephardt postdoctoral fellowship, and Individual National Research Service Award F32 AI072816 (to L.W.C.).

² Address correspondence and reprint requests to Dr. Dario A. A. Vignali, Department of Immunology, Mailstop #351, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678. E-mail address: vignali.lab{at}stjude.org

³ Abbreviations used in this paper: T_reg, regulatory T cell; CT, cycle threshold; T_conv, conventional effector T cell; T_sup, suppressed target T cell.

⁴ The online version of this article contains supplemental material.