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Brief Definitive Report

¹ Yale University School of Medicine, New Haven, CT 06520
² Howard Hughes Medical Institute, New Haven, CT 06520

Address correspondence to Richard A. Flavell, FRS Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520. Phone: 203-737-2216; Fax: 203-737-2958; E-mail: fran.manzo{at}yale.edu

Regulation by transforming growth factor (TGF)-ß plays an important role in immune homeostasis. TGF-ß inhibits T cell functions by blocking both proliferation and differentiation. Here we show that TGF-ß blocks Th1 differentiation by inhibiting the expression of T-bet, the apparent masterregulator of T helper (Th)1 differentiation. Restoration of T-bet expression through retroviral transduction of T-bet into developing Th1 cells abrogated the inhibitory effect of TGF-ß. In addition, we show that, contrary to prior suggestions, downregulation of interleukin 12 receptor ß2 chain is not key to the TGF-ß–mediated effect. Furthermore, we show that the direct inhibitory effect of TGF-ß on T cells is responsible, at least in part, for the inability of BALB/c mice to mount a Leishmania-specific Th1 response and to clear Leishmanial infection.

Key Words: T cell • differentiation • TGF-ß • T-bet • Leishmania

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