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Cutting Edge: Expression of TNFR2 Defines a Maximally Suppressive Subset of Mouse CD4⁺CD25⁺FoxP3⁺ T Regulatory Cells: Applicability to Tumor-Infiltrating T Regulatory Cells¹

Xin Chen^2,*, Jeffrey J. Subleski, Heather Kopf, O. M. Zack Howard, Daniela N. Männel and Joost J. Oppenheim

^* Basic Research Program, SAIC-Frederick, Inc. National Cancer Institute (NCI)-Frederick, Laboratory of Experimental Immunology, Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, Center for Cancer Research, NCI-Frederick, Frederick, MD 21702; and Institute of Immunology, University of Regensburg, Regensburg, Germany

TNFR2 is predominantly expressed by a subset of human and mouse CD4⁺CD25⁺FoxP3⁺ T regulatory cells (Tregs). In this study, we characterized the phenotype and function of TNFR2⁺ Tregs in peripheral lymphoid tissues of normal and tumor-bearing C57BL/6 mice. We found that TNFR2 was expressed on 30–40% of the Tregs of the peripheral activated/memory subset that were most highly suppressive. In contrast, TNFR2^– Tregs exhibited the phenotype of naive cells and only had minimal suppressive activity. Although not typically considered to be Tregs, CD4⁺CD25^–TNFR2⁺ cells nevertheless possessed moderate suppressive activity. Strikingly, the suppressive activity of TNFR2⁺ Tregs was considerably more potent than that of reportedly highly suppressive CD103⁺ Tregs. In the Lewis lung carcinoma model, more highly suppressive TNFR2⁺ Tregs accumulated intratumorally than in the periphery. Thus, TNFR2 identifies a unique subset of mouse Tregs with an activated/memory phenotype and maximal suppressive activity that may account for tumor-infiltrating lymphocyte-mediated immune evasion by tumors.

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 project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract N01-CO-12400. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Additional funding was provided by a Deutsche Forschungsgemeinschaft Grant Ma760/16-1. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.

² Address correspondence and reprint requests to Dr. Xin Chen, Basic Research Program, SAIC-Frederick, Inc. Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, NCI-Frederick. P.O. Box B, Building 560, Room 31-19, Frederick, MD 21702-1201. E-mail address: chenxin{at}mail.nih.gov

³ Abbreviations used in this paper: Treg, CD4⁺CD25⁺ T regulatory cell; GITR, glucocorticoid-induced TNFR family-related protein; LLC, Lewis lung carcinoma; LN, lymph node; Teff, CD4⁺CD25^– T effector cell; TIL, tumor-infiltrating lymphocyte.

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