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CD28 Controls Differentiation of Regulatory T Cells from Naive CD4 T Cells¹

Fei Guo^*, Cristina Iclozan^*, Woong-Kyung Suh, Claudio Anasetti^*, and Xue-Zhong Yu^2,*,

^* Immunology and Blood and Marrow Transplantation Programs, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Immune Regulation Laboratory, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada; and Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL 33612

CD28 is required for the development of regulatory T cells (Tregs; CD4⁺CD25⁺Foxp3⁺) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using wild-type, CD28-, ICOS-, or CD28/ICOS-double knockout mice on C57BL/6 background as T cell sources, we found that CD28 is essential, whereas ICOS is dispensable, for the development and homeostasis of Tregs. Furthermore, the differentiation of Tregs from naive CD4⁺CD25^– T cells in vivo also depends on CD28. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb-blocked Treg differentiation from wild-type CD4⁺CD25^– T cells and addition of IL-2 restored Treg differentiation from CD28^–/– T cells. Other common -chain cytokines, IL-4, IL-7, or IL-15, do not share such a role with IL-2. Although CD28 is required for the differentiation of Tregs from naive T cells, already generated Tregs do not depend on CD28 to exert their suppressive function. Our study reveals a new aspect of CD28 function in regulating T cell response.

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 in part by National Institutes of Health Grants AI 63553, CA 118116 (to X.-Z. Y.), and AI 51693 (to C. A.). X.-Z.Y. is a recipient of New Investigator Award supported by American Society for Blood and Bone Marrow Transplantation.

² Address correspondence and reprint requests to Dr. Xue-Zhong Yu, H. Lee Moffitt Cancer Center and Research Institute, Mailbox SRB-2, 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: YuXZ{at}moffitt.usf.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; nTreg, naturally occurring Treg; Tg, transgenic; iTreg, induced Treg; KO, knockout; WT, wild type; B6, C57BL/6 mice; KI, knock-in; Itk, IL-2-inducible T cell kinase.

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