After activation by antigen-presenting cells (APC), naïve, antigen-specific CD4+ T cells differentiate into effector T cells. More than two decades ago, Coffman and Mosman first discovered the heterogeneity of effector T cells, which were then named as Th1 or Th2 cells. Th1 and Th2 cells are differentially induced and regulate immunity against intracellular and extracellular pathogens, respectively, as well as immunopathologies such as autoimmunity and allergy. The Th1/Th2 dichotomy has dominated the field of immune regulation until five years ago when IL-17-expressing T cells were proposed to be a third lineage of helper T cells. Th17 cell differentiation can be induced by the combination of TGFβ and IL-6 [1]. Inhibition of TGFβ signaling in vivo was shown to substantially reduce Th17 cell generation in experimental autoimmune encephalomyelitis (EAE) model. In support of a critical role of TGFβ signaling in T cells, deficiency in TGFβ signaling or Smad2, a transcription factor downstream of TGFβ signaling also inhibited Th17 cell generation. It has been recently debated whether TGFβ is absolutely required for Th17 cell generation. It was first shown that murine naïve T cells can be induced into Th17 cells by use of IL-1, IL-6 and IL-23 in the absence of exogenous TGFβ. Interestingly, Th17 cells generated under this condition highly expressed IL-22, compared with Th17 cells induced by TGFβ and IL-6. However, anti-TGFβ antibody inhibited this differentiation, suggesting that endogenous TGFβ was necessary [2]. Subsequently, the induction of Th17 cells by use of the same cytokines was also reported by another group, but it was TGFβ independent. Moreover, Th17 cells generated in this manner produced IFNγ and expressed transcription factor T-bet as well as CXCR3, all Th1 products. And these Th17 cells were found more potent in induction of EAE than those induced in the presence of TGFβ and IL-6 [2]. A third group found that IL-23 signaling significantly upregulates the expression of TGFβ3 in T cells [2]. TGFβ3 in the presence of IL-6 induced the “pathogenic” Th17 signatures. TGFβ3 is regarded as a weaker cytokine than TGFβ1. Perhaps at the same concentration that TGFβ1 can induce Foxp3 expression, TGFβ3 is unable. It remains to be tested whether high dose of TGFβ3 can induce regulatory phenotypes in Th17 cells. Nonetheless, this study suggests that TGFβ1 and TGFβ3 work in concert or in sequence to promote Th17 cell differentiation. This idea has not been genetically tested yet in vivo. These latest work add a layer of complexity to the Th17 cell biology. It can be postulated that Th17 cells come in different flavors. In TGFβ-rich environment, eg, gut [2], Th17 cells may be less pathogenic or even regulatory like, whereas during extensive inflammation under the influence of proinflammatory cytokines, they may be more pathogenic, producing cytokines such as IFNγ, GM-CSF and IL-22. What intrinsic mechanisms that differentially target different sets of genes in these two types of Th17 cell differentiation are unknown. Whether these subtypes of Th17 cells are stable and can be interswitched also needs to be addressed in the future studies.

Since its discovery, Th17 cell generation and function has been linked with many environmental conditions. For example, earlier work showed an import role of Ahr, a receptor for environmental toxins, in Th17 generation [1]. On the other hand, retinoic acid (RA) and vitamin D inhibit Th17 cell differentiation [2].