Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation

J Exp Med. 2002 Jun 3;195(11):1499-505. doi: 10.1084/jem.20012076.

Abstract

Regulation by transforming growth factor (TGF)-beta plays an important role in immune homeostasis. TGF-beta inhibits T cell functions by blocking both proliferation and differentiation. Here we show that TGF-beta 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-beta. In addition, we show that, contrary to prior suggestions, downregulation of interleukin 12 receptor beta2 chain is not key to the TGF-beta-mediated effect. Furthermore, we show that the direct inhibitory effect of TGF-beta 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Foot / parasitology
  • Foot / pathology
  • Gene Expression Regulation / drug effects
  • Leishmania major / immunology
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Interleukin / antagonists & inhibitors
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-12
  • T-Box Domain Proteins
  • T-bet Transcription Factor
  • Th1 Cells / cytology*
  • Th1 Cells / drug effects*
  • Th1 Cells / immunology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Il12rb2 protein, mouse
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • T-Box Domain Proteins
  • T-bet Transcription Factor
  • Transcription Factors
  • Transforming Growth Factor beta