Morita et al (1) reported that naive CD4+ T cells from DBA/1 mice have a dichotomous response to transforming growth factor β (TGFβ) signaling, which leads to skewed differentiation of Th17 cells but reduced differentiation of induced Treg cells. Of note, in order to differentiate into Th17 cells upon T cell receptor activation, naive CD4+ T cells required signaling from interleukin-6 (IL-6) together with TGFβ (1).
However, Ghoreschi et al (2) have reported that Th17 cell differentiation could occur in the absence of TGFβ signaling. Since TGFβ1 plays a crucial role in murine Th17 cell differentiation, transgenic expression of mutant TGFβ subunit receptor II (CD4dnTGF-βRII) in T cells may disturb the generation of Th17 cells in the setting of experimental allergic encephalomyelitis (EAE), and Ghoreschi and colleagues investigated whether Th17 cells were present in vivo in a mouse model of EAE. They found no difference in absolute numbers of IL-17–producing CD4+ cells between wild-type and CD4dnTGF-βRII mice. This result was confirmed in further studies using mice that lack TGFβ receptor subunit I in T cells (2). In vitro, anti-TGFβ antibodies interfered with the Th17 cell differentiation induced by the combination of TGFβ1/IL-6/IL-1β, whereas they had no apparent effect on Th17 cell differentiation induced by IL-23/IL-6/IL-1β. The antibodies blocked FoxP3 expression and Th17 cell differentiation by exogenous TGFβ1 but had no impact on IL-23–dependent Th17 cell differentiation. Furthermore, IL-6 and IL-1β induced IL-23 receptor (IL-23R) messenger RNA expression independently of TGFβ; expression was increased with addition of IL-23. Moreover, IL-6 and IL-23 in combination with IL-1β effectively induced transcription and epigenetic modification of the IL-17A/IL-17F and Rorc loci in the absence of TGFβ1. Th1 cells positive for T-bet and retinoic acid–related orphan receptor γt cells were present, and adoptively transferred Th17 cells generated with IL-23 without TGFβ1 were pathogenic in the EAE model (2).
In fact, Th17 cells derived in the presence of IL-23 are likely to have significant pathogenic potential. They express T-bet, IL-18RI, and CXCR3, which is important for development of EAE or trafficking of T cells to sites of inflammation. However, TGFβ1 was able to suppress not only T-bet expression, but also IL-23R expression and IL-23–mediated IL-22 production (2). Intriguingly, IL-23 has been shown to be a potent inducer of IL-22 (3). Ghoreschi et al suggest that Th17 cells seem to represent heterogeneous populations including the offspring of Th17(β) or Th17(23) cells with varying trafficking profiles and diverse capabilities to induce autoimmune disease (2). In conclusion, they reported an alternative mode for Th17 cell differentiation and emphasized the importance of IL-23 in EAE. Nevertheless, their data were obtained from the EAE animal model, and further studies with a large sample size and precise methodology are needed to determine the exact mechanisms of Th17 cell differentiation in autoimmune diseases, especially in human systems.