The Journal of Experimental Medicine
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Published 16 June 2003. doi:10.1084/jem.20021170
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© Rockefeller University Press, 0022-1007/2003/6/1689 $5.00
The Journal of Experimental Medicine, Volume 197, Number 12, 1689-1699

Transforming Growth Factor ß Blocks Tec Kinase Phosphorylation, Ca2+ Influx, and NFATc Translocation Causing Inhibition of T Cell Differentiation

Chang-Hung Chen1, Carole Seguin-Devaux2, Nancy A. Burke3, Timothy B. Oriss2, Simon C. Watkins3, Neil Clipstone4 and Anuradha Ray2

1 Vion Pharmaceuticals, Incorporated, New Haven, CT 06511
2 Department of Medicine, Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
3 Department of Cell Biology and Physiology and Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
4 Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611

Address correspondence to Dr. Anuradha Ray, Department of Medicine, Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Ave., MUH 628 NW, Pittsburgh, PA 15213. Phone: 412-802-3191; Fax: 412-692-2260; E-mail: raya{at}pitt.edu

Transforming growth factor (TGF)-ß inhibits T cell proliferation and differentiation. TGF-ß 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-ß 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-ß 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-ß limits T cell differentiation along both the Th1 and Th2 lineages.

Key Words: TGF-ß • T cell • NFAT • Itk • calcium


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