Transforming growth factor‐β1 enhances the interferon‐γ‐dependent, interleukin‐12‐independent pathway of T helper 1 cell differentiation

Abstract

SummaryTransforming growth factor (TGF)-b, 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-b 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-c (IFN-c)-producing cells. T cells primed with TGF-b secreted IFN-c 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-b-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-c. TGF-b-mediated enhancement of the IFN-c-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-b 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-b-producing T cells for the treatment of autoimmune disorders.

Effects of Exogenous Transforming Growth Factor β onTrypanosoma congolenseInfection in Mice

“…The induction of a parasite antigen-specific Th1 cell response in vitro and a net type I cytokine environment in vivo by TGF-␤1 pretreatment was observed in early-stage-infected mice. This is in agreement with recent reports indicating that while TGF-␤1 inhibits the development of IL-4-producing cells, it also enhances the development of IFN-␥-producing cells (8,33). The resultant proinflammatory environment could contribute to parasite control (7,17) and may explain why TGF-␤1-pretreated mice exhibit lower parasitemia and reduced pathology.…”

“…Indeed, in agreement with previous reports that correlate the survival of T. congolense-infected mice with their ability to control the first parasitemic peak (24), treatment of mice with TGF-␤1 retarded the rate of parasite proliferation and prolonged their survival. Exogenous TGF-␤1 seems to induce beneficial systemic effects mainly during the early phase of T. congolense infection, as described for other infection models (26,33). During that period, TGF-␤1-pretreated mice effectively controlled the development of pathology.…”

TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

“…TGF-b can directly suppress IL-12-dependent T H 1 differentiation through mechanisms that may include both the suppression of the transcription factor Tbet, a master regulator of Th1 gene expression Lin et al, 2005), and the downregulation of IL-12 responsiveness (Gorham et al, 1998;Pardoux et al, 1999). However, the development of IL-12-independent differentiation toward T H 1 is actually enhanced by TGF-b (Smeltz et al, 2005), an observation that again reveals the context-dependent activity of TGF-b, and also provides a note of caution regarding the application of TGF-b to augment the production of T cells with a regulatory phenotype (see below).…”

Identification of a New Pathway for Th1 Cell Development Induced by Cooperative Stimulation with IL-4 and TGF-β

“…However, the effects of TGF-b on Th1 cell development are less clear. It is known that TGF-b inhibits IL-12-dependent Th1 cell differentiation, whereas IFN-g-induced Th1 cell development does not decrease, but rather becomes enhanced, in the presence of TGF-b (24).…”