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OX40/OX40L Costimulation Affects Induction of Foxp3⁺ Regulatory T Cells in Part by Expanding Memory T Cells In Vivo¹

Xiang Xiao^*, Alexander Kroemer^*, Wenda Gao^*, Naoto Ishii, Gulcin Demirci^* and Xian Chang Li^2,*

^* Harvard Medical School, Transplant Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02115; and Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan

OX40 is a member of the TNFR superfamily and has potent T cell costimulatory activities. OX40 also inhibits the induction of Foxp3⁺ regulatory T cells (Tregs) from T effector cells, but the precise mechanism of such inhibition remains unknown. In the present study, we found that CD4⁺ T effector cells from OX40 ligand-transgenic (OX40Ltg) mice are highly resistant to TGF-β mediated induction of Foxp3⁺ Tregs, whereas wild-type B6 and OX40 knockout CD4⁺ T effector cells can be readily converted to Foxp3⁺ T cells. We also found that CD4⁺ T effector cells from OX40Ltg mice are heterogeneous and contain a large population of CD44^highCD62L^– memory T cells. Analysis of purified OX40Ltg naive and memory CD4⁺ T effector cells showed that memory CD4⁺ T cells not only resist the induction of Foxp3⁺ T cells but also actively suppress the conversion of naive CD4⁺ T effector cells to Foxp3⁺ Tregs. This suppression is mediated by the production of IFN- by memory T cells but not by cell-cell contact and also involves the induction of T-bet. Importantly, memory CD4⁺ T cells have a broad impact on the induction of Foxp3⁺ Tregs regardless of their origins and Ag specificities. Our data suggest that one of the mechanisms by which OX40 inhibits the induction of Foxp3⁺ Tregs is by inducing memory T cells in vivo. This finding may have important clinical implications in tolerance induction to transplanted tissues.

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 grants from the National Institute of Health (R01 057409 and R01 070315) and the Juvenile Diabetes Research Foundation International (1-2006-659).

² Address correspondence and reprint requests to Dr. Xian C. Li, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, HIM-1025, Boston, MA 02215; E-mail address: xli{at}bidmc.harvard.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; B6, C57BL/6; foxp3gfp, Foxp3-GFP knockin mice on B6 background; KO, knockout; OX40L, OX40 ligand; OX40Ltg, OX40L transgenic; OX40KO, OX40 knockout; SN, supernatant; Wt, wild type.

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