A costimulation-initiated signaling pathway regulates NFATc1 transcription in T lymphocytes

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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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 Cγ1 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.

Original languageEnglish (US)
Pages (from-to)1096-1103
Number of pages8
JournalJournal of Immunology
Volume179
Issue number2
DOIs
StatePublished - Jul 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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