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Activation of NF-B1 by OX40 Contributes to Antigen-Driven T Cell Expansion and Survival¹

Jianxun Song^2,*,, Takanori So^2,* and Michael Croft^3,*

^* Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and Institute of Immunology, Peoples Liberation Army, Third Military Medical University, Chongqing, China

The costimulatory molecule OX40 (CD134) is required in many instances for effective T cell-mediated immunity, controlling proliferation, and survival of T cells after encountering specific Ag. We previously found that the functional targets of OX40 are survivin and aurora B that regulate proliferation and Bcl-2 antiapoptotic family members that regulate survival. However, the intracellular pathways from OX40 that mediate these effects are unclear. In this study, we show that OX40 signaling can target the canonical NF-B (NF-B1) pathway in peripheral Ag-responding CD4 T cells. Phosphorylation of IB, nuclear translocation of NF-B1/p50 and RelA, and NF-B1 activity, are impaired in OX40-deficient T cells. Retroviral transduction of active IB kinase that constitutively activates NF-B1 rescues the poor expansion and survival of OX40-deficient T cells, directly correlating with increased expression and activity of survivin, aurora B, and Bcl-2 family members. Moreover, active IB kinase expression alone is sufficient to restore the defective expansion and survival of OX40-deficient T cells in vivo when responding to Ag. Thus, OX40 signals regulate T cell number and viability through the NF-B1 pathway that controls expression and activity of intracellular targets for proliferation and survival.

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 Institutes of Health (AI50498 and AI49453 to M.C.) and the Universitywide AIDS Research Program (to J.S.). This is manuscript 911 from the La Jolla Institute for Allergy and Immunology.

² J.S. and T.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Michael Croft, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: mick{at}liai.org

⁴ Abbreviations used in this paper: PKB, protein kinase B; MCC, moth cytochrome c; IKK, IB kinase; CA, constitutively; WT, wild type; KO, knockout.

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