TCR/CD28-stimulated actin dynamics are required for NFAT1-mediated transcription of c-rel leading to CD28 response element activation

Jeffrey Nolz, Martin E. Fernandez-Zapico, Daniel D. Billadeau

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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-κB. 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.

Original languageEnglish (US)
Pages (from-to)1104-1112
Number of pages9
JournalJournal of Immunology
Volume179
Issue number2
Publication statusPublished - Jul 15 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

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