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OX40-Mediated Differentiation to Effector Function Requires IL-2 Receptor Signaling but Not CD28, CD40, IL-12R2, or T-bet¹

Cortny A. Williams^*, Susan E. Murray^*, Andrew D. Weinberg and David C. Parker^2,*

^* Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239; and Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213

Ag-specific CD4 T cells transferred into unirradiated Ag-bearing recipients proliferate, but survival and accumulation of proliferating cells is not extensive and the donor cells do not acquire effector functions. We previously showed that a single costimulatory signal delivered by an agonist Ab to OX40 (CD134) promotes accumulation of proliferating cells and promotes differentiation to effector CD4 T cells capable of secreting IFN-. In this study, we determined whether OX40 costimulation requires supporting costimulatory or differentiation signals to drive acquisition of effector T cell function. We report that OX40 engagement drives effector T cell differentiation in the absence of CD28 and CD40 signals. Two important regulators of Th1 differentiation, IL-12R and T-bet, also are not required for acquisition of effector function in CD4 T cells responsive to OX40 stimulation. Finally, we show that CD25-deficient CD4 T cells produce little IFN- in the presence of OX40 costimulation compared with wild type, suggesting that IL-2R signaling is required for efficient OX40-mediated differentiation to IFN- secretion.

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 AI50823 (to D.C.P.) and CA81383 (to A.D.W.) from the National Institutes of Health. C.A.W. was supported as a trainee in the Molecular Hematology Training Program, Grant T32-HL007781.

² Address correspondence and reprint requests to Dr. David C. Parker, Department of Molecular Microbiology and Immunology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L220, Portland, OR 97239. E-mail address: parkerd{at}ohsu.edu

³ Abbreviations used in this paper: PCC, pigeon cytochrome c; DC, dendritic cell.

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