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A Costimulation-Initiated Signaling Pathway Regulates NFATc1 Transcription in T Lymphocytes¹

Roza I. Nurieva^*, Sergei Chuvpilo, Eric D. Wieder^*, Keith B. Elkon, Richard Locksley, Edgar Serfling and Chen Dong^2,*

^* Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030; Institute of Pathology, Department of Molecular Pathology, University of Würzburg, Würzburg, Germany; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195; and Department of Medicine and Department of Microbiology/Immunology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94110

T cell activation and differentiation is accompanied and mediated by transcriptional reprogramming. The NFATc1 transcription factor is strongly induced upon T cell activation and controls numerous genes involved in the T cell effector function. However, its regulation by physiological stimuli in primary T cells has not been well understood. We previously found that ICOS synergizes with TCR and CD28 to greatly enhance NFATc1 expression in primary T cells. In this study, we have examined the signaling mechanisms whereby costimulation regulates NFATc1 expression. We found that CD28 and ICOS regulate sustained PI3K activity in primary T cells, which is required for NFATc1 up-regulation. CD28 and ICOS costimulation, possibly through Itk, a Tec kinase downstream of the PI3K, enhanced phosphorylation of phospholipase C1 and increased and sustained Ca²⁺ flux in T cells. Costimulation of T cells potentiated transcription of the Nfatc1 gene P1 promoter in a PI3K-dependent manner. This work demonstrates an important role for costimulatory receptors in sustaining T cell activation programs leading to Nfatc1 gene transcription and has implications in our understanding of the immune response and tolerance.

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 is supported in part by grants from the National Institute of Health (to C.D.) and from the Deutsche Forschungsgemeinschaft, the Wilhelm Sander foundation, and the Scheel Foundation for Cancer Research (to E.S.). R.I.N. is a recipient of an Arthritis Foundation postdoctoral fellowship and an American Heart Association Scientist Development Grant, R.L. is a Howard Hughes Medical Institute investigator, and C.D. received an Investigator award from the Cancer Research Institute and a Trust Fellowship from M.D. Anderson Cancer Center.

² Address correspondence and reprint requests to Dr. Chen Dong, Department of Immunology, M.D. Anderson Cancer Center, 7455 Fannin, Unit 906, Houston, TX 77030. E-mail address: cdong{at}mdanderson.org

³ Abbreviations used in this paper: PLC, phospholipase C; AM, acetoxymethyl ester; B6, C57BL/6; PIP3, phosphatidylinositol 3,4,5-triphosphate; PH, pleckstrin homology; PKB, protein kinase B.

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