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TCR/CD28-Stimulated Actin Dynamics Are Required for NFAT1-Mediated Transcription of c-rel Leading to CD28 Response Element Activation¹

Jeffrey C. Nolz^*, Martin E. Fernandez-Zapico and Daniel D. Billadeau^2,*,

^* Department of Immunology, Gastroenterology Research Unit, and Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN 55905

TCR/CD28 engagement triggers the initiation of a variety of signal transduction pathways that lead to changes in gene transcription. Although reorganization of the actin cytoskeleton is required for T cell activation, the molecular pathways controlled by the actin cytoskeleton are ill defined. To this end, we analyzed TCR/CD28-stimulated signaling pathways in cytochalasin D-treated T cells to determine the cytoskeletal requirements for T cell activation. Cytochalasin D treatment impaired T cell activation by causing a reduction in TCR/CD28-mediated calcium flux, and blocked activation of two regulatory elements within the IL-2 promoter, NFAT/AP-1 and CD28RE/AP. Treatment had no effect on signaling leading to the activation of either AP-1 or NF-B. Significantly, we found that NFAT1 is required for optimal c-rel up-regulation in response to TCR/CD28 stimulation. In fact, NFAT1 could be detected bound at the c-rel promoter in response to TCR/CD28 stimulation, and targeting of NFAT1 using RNA interference in human CD4⁺ T cells abrogated c-rel transcription. Overall, these findings establish that disrupting actin cytoskeletal dynamics impairs TCR/CD28-mediated calcium flux required for NFAT1-mediated c-rel transcription and, thus, activation of the CD28RE/AP.

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 the Mayo Foundation and Grant R01-AI065474 from the National Institutes of Health (to D.D.B.) and by a Predoctoral Immunology Training Grant T32-AI07425 (to J.C.N.) from the National Institutes of Health. M.E.F.-Z. was supported by Grant CA125127 from the National Institutes of Health, Mayo Clinic Pancreatic SPORE Grant CA102701, University of Iowa/Mayo Clinic Lymphoma SPORE Grant CA097274, the Division of Gastroenterology, and the Mayo Clinic Cancer Center.

² Address correspondence and reprint requests to Dr. Daniel D. Billadeau, Department of Immunology and Division of Oncology Research, 200 First Street SW, Rochester, MN 55905. E-mail address: billadeau.daniel{at}mayo.edu

³ Abbreviations used in this paper: PLC, phospholipase C; ChIP, chromatin immunoprecipitation; IP₃, inositol 1,4,5-triphosphate; SEE, staphylococcal enterotoxin E; IKK, IB kinase; siRNA, small interfering; ER, endoplasmic reticulum; CRAC, calcium release-activated calcium.

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