Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 197, Issue 12, Pages 1689-1699Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20021170
Keywords
TGF-beta; T cell; NFAT; Itk; calcium
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Funding
- NHLBI NIH HHS [P50 HL056389, P50-HL56389, HL 60995] Funding Source: Medline
- NIAID NIH HHS [AI 48927, R01 AI048927] Funding Source: Medline
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Transforming growth factor (TGV)-beta inhibits T cell proliferation and differentiation. TGF-beta 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-beta 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-beta 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-beta limits T cell differentiation along both the Th1 and Th2 lineages.
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