Transforming growth factor β blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation

Chang Hung Chen, Carole Seguin-Devaux, Nancy A. Burke, Timothy B. Oriss, Simon C. Watkins, Neil Clipstone, Anuradha Ray*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

120 Citations (Scopus)

Abstract

Transforming growth factor (TGF)-β inhibits T cell proliferation and differentiation. TGF-β has been shown to inhibit the expression of transcription factors such as GATA-3 and T-bet that play important roles in T cell differentiation. Here we show that TGF-β inhibits T cell differentiation at a more proximal step. An early event during T cell activation is increased intracellular calcium levels. Calcium influx in activated T cells and the subsequent activation of transcription factors such as NFATc, events essential for T cell differentiation, are modulated by the Tec kinases that are downstream of the T cell receptor and CD28. We show that in stimulated CD4+ T cells, TGF-β inhibits phosphorylation and activation of the Tec kinase Itk, increase in intracellular Ca2+ levels, NFATc translocation, and activation of the mitogen-activated protein kinase ERK that together regulate T cell differentiation. Our studies suggest that by inhibiting Itk, and consequently Ca2+ influx, TGF-β limits T cell differentiation along both the Th1 and Th2 lineages.

Original languageEnglish
Pages (from-to)1689-1699
Number of pages11
JournalJournal of Experimental Medicine
Volume197
Issue number12
DOIs
Publication statusPublished - 16 Jun 2003
Externally publishedYes

Keywords

  • Calcium
  • Itk
  • NFAT
  • T cell
  • TGF-β

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