Th17 cells: An orphan with influence (2007)

The known peripheral T-cell compartment has recently expanded by the identification of yet another CD4 effector T-cell subpopulation, the so-called Th17T cells (a reference to their signature cytokine interleukin-17 (IL-17)), which appear to be important in the pathogenesis of autoimmune diseases. Intriguingly, a recent study has shown that Th17 differentiation is specified by a transcription factor that is also instrumental in lymphoid organogenesis.1 IL-17-producing T cells have been shown to play leading roles in diseases such as autoimmune arthritis and experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. Previously, there had been confusion about whether IL-17-producing T cells represented a variation of Th1 cells; however, the absence of any lineage defining transcription factor needed for Th1 or Th2 differentiation2,3 as well as the identification of IL-6 and transforming growth factor-β (TGF-β) as the crucial differentiation factors for these cells,4 firmly established Th17T cells as an independent T-cell lineage. Ivanov et al.1 have now identified the nuclear retinoic acid-related orphan receptor RORγt as the transcription factor specifying the Th17 lineage. There is as yet no in vivo ligand known for this transcription factor. RORγt appeared in the limelight before, when Dan Littman's group described its link to the generation of fetal lymphoid tissue inducer (LTi) cells.5 Using mice with green fluorescent protein (GFP) reporter cDNA knocked in at the site for RORγt translation, GFP expression, reporting RORγt, was detected in a population of hematopoetic cells in the developing fetus that colonizes the anlagen for lymph nodes and Peyer's patches. LTi cells drive the development of lymph nodes, Peyer's patches and nasal-associated tissue. Mice that lack RORγt lack lymph nodes, Peyer's patches and LTi, but what exactly the function of RORγt is in the generation of LTi is currently not known. In the Cell paper, Littman's group used the same reporter mice and found somewhat lower levels of reporter expression in about 10% of CD4+ αβ T cells and 50% of γδ T cells in the lamina propria of the small intestine in adult mice. No reporter expression was found outside the intestine and indeed the proportion of Th17T cells detectable in lymphoid organs of specific pathogen-free (SPF) mice is well below 1%. GFP expression coincided with staining for IL-17. In mice homozygous for the GFP reporter, which disables RORγt expression, there was a considerable reduction in GFP as well as IL-17 expressing αβ T cells and γδ T cells expressing GFP or IL-17 were not found. These data suggest that RORγt might be involved in the differentiation of IL-17-producing Th17T cells. In line with this, CD4 T cells from RORγ-deficient mice showed a drastically reduced ability for polarization to Th17T cells under conditions in vitro that favor their differentiation, that is in the presence of IL-6 and TGF-β. More conclusively, transduction of T cells with retroviral constructs delivering RORγt in the absence of polarizing factors for Th17 differentiation resulted in IL-17 expression in a substantial fraction of the transduced cells, indicating that expression of this transcription factor is sufficient to drive differentiation of the Th17 effector population. CD4T cells isolated from the lamina propria of IL-6-deficient mice did not express RORγt, suggesting that IL-6 is involved in the upregulation of this transcription factor. It is as yet unclear what the individual contributions of IL-6 and TGF-β are in the differentiation step to Th17, but both of them are obligatory and the role of TGF-β goes beyond its known suppressive effect on Th1 and Th2 differentiation. Finally, this paper shows that the induction of EAE, which is crucially dependent on Th17T cells, is prevented in mice deficient for RORγ expression. Although this study clearly defines RORγt as an essential factor for establishing the Th17 lineage, a number of intriguing questions remain unresolved. First, the seemingly constitutive presence of Th17T cells in the intestine raises questions about their functional role in this location. Clearly, the dominant view held that Th17 are a pro-inflammatory T-cell subset with a major pathogenic role in many autoimmune diseases does not fit easily with their seemingly constitutive presence in the gut of healthy mice. However, IL-17 stimulates tight junction formation and mucin secretion, which could indicate a positive role in the gut by protecting mucosal barrier function. Th17T cells have recently been shown to secrete the cytokine IL-22 in addition to IL-17.6 IL-22 production is upregulated by IL-23, a pro-inflammatory cytokine made by dendritic cells and macrophages. As IL-23 is linked to gut disorders such as inflammatory bowel disease,7 could it be that the production of IL-22, rather than IL-17, by Th17 is involved in gut pathology? It will be interesting to see whether RORγt expression is also needed for the IL-22 phenotype of Th17T cells. Furthermore, it remains to be seen whether IL-23 reciprocally regulates IL-17 vs IL-22 expression and thereby alters functional activity in the gut. Certainly, the digestive system in addition to skin and respiratory system expresses receptors for IL-22. It would also be important to define whether RORγt is essential to maintain the expression of Th17 cytokines or whether, like GATA-3, it is dispensable for maintenance of cytokines, once the cells are fully activated. Thus, while the absence of RORγt prevents the development of EAE, we do not know at present whether continued RORγt expression is required to maintain the pathogenic function of Th17 cells once autoimmunity is initiated. These are questions that could all be addressed with the help of the RORγt reporter mice.