Control of Treg and T_H17 cell differentiation by the aryl hydrocarbon receptor

Quintana et al. Nature, May 2008; 453:65-71

Speaker: 李建勳                                                  Time:14:00-15:00 12/10 2008

Commentator: 孫昭玲 老師                               Place: Room 601

        Regulatory T (Treg) and T helper 17 (Th17) cells are two lymphocyte subsets playing opposing roles in immune responses, and imbalanced T cell differentiation along the Treg-Th17 axis may result in many diseases. For example, Treg-mediated immunosuppression potentiates virus persistence and cancer development, while Th17 cells exacerbate inflammatory and autoimmune diseases. Previous studies have emphasized that combination of cytokines in the microenvironment can influence the balance of Treg-Th17 differentiation, but it is largely unknown what other factors are involved. In this article, the authors reveal that aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor that senses environmental toxins and endogenous metabolites, can regulate Treg-Th17 differentiation. Interestingly in the mouse model of experimental autoimmune encephalitis (EAE), treatment with two AHR ligands, TCDD and FICZ, leads to totally different outcomes. TCDD suppresses EAE through increasing Treg cells and TGF-β production, but FICZ worsens EAE by increasing Th17 cells and production of IL-17. Further studies show that TCDD induces AHR binding to the Foxp3 promoter and expression of Foxp3, promoting T cell differentiation toward Treg. On the other hand, FICZ interferes with Treg differentiation triggered by TGF-b, and significantly enhances expression of Th17-specific genes, such as ROR-gt, IL-17 and IL-22, in CD4⁺ T cells treated with IL-6 and TGF-b. Therefore, AHR can modulate Treg-Th17 differentiation, depending on ligands of the receptor and the context of cytokines. Thus AHR could serve as a linkage between environmental factors and autoimmune diseases, and also a potential therapeutic target.

Reference:

1.      Ho et al. The aryl hydrocarbon receptor: a regulator of Th17 and Treg cell development in disease. Cell Research. (2008) 18:605-608.

2.      Stevens et al. T cells hang in the balance. Nature news & views. (2008) Vol 453.