Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation.
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.
Gorelik
Leonid
L
Yale University School of Medicine, New Haven, CT 06520, USA.
Constant
Stephanie
S
Flavell
Richard A
RA
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D005528:Foot / Q000469:parasitology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D018320:Leishmania major / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000378:metabolism; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000098815:T-bet Transcription Factor
C508443:Il12rb2 protein, mouse; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta