Transforming growth factor-beta1 enhances the interferon-gamma-dependent, interleukin-12-independent pathway of T helper 1 cell differentiation.
Transforming growth factor (TGF)-beta, a pleiotropic cytokine that has multiple effects on immune responses, has been shown to inhibit interleukin (IL)-4/GATA-3 expression as well as T helper 2 (Th2) differentiation. Consistent with these reports, we found that priming T cells from DO11.10 transgenic mice with antigen in the presence of TGF-beta inhibited GATA-3 expression and the development of IL-4-producing T cells. Unexpectedly, the inhibition of Th2 development was accompanied by a substantial increase in the number of interferon-gamma (IFN-gamma)-producing cells. T cells primed with TGF-beta secreted IFN-gamma in response to both T-cell receptor ligation and IL-12/IL-18 stimulation, and expressed high levels of T-bet and low levels of GATA-3. The TGF-beta-mediated enhancement of T helper 1 (Th1) priming was independent of IL-12 and signal transducer and activator of transcription (STAT)-4, but required endogenous IFN-gamma. TGF-beta-mediated enhancement of the IFN-gamma-dependent, IL-12-independent pathway of Th1 priming was mediated primarily by the inhibition of IL-4 produced by memory/activated T cells in the unfractionated CD4+ responder population. Nevertheless, TGF-beta did not inhibit this pathway of Th1 differentiation when purified naive CD4+ T cells were used as responders. These data have important implications for strategies being considered for the use of TGF-beta-producing T cells for the treatment of autoimmune disorders.
Smeltz
Ronald B
RB
Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Chen
June
J
Shevach
Ethan M
EM
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000098815:T-bet Transcription Factor
D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma