T cells: Tuning T cells through the aryl hydrocarbon receptor

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The aryl hydrocarbon receptor (AHR) transcription factor is an important ligand-dependent regulator of interleukin-17 (IL-17)-producing CD4⁺ T helper cells (T_H17) and regulatory T (T_Reg) cell populations.

Based on their respective roles in immune tolerance and inflammation, regulatory T (T_Reg) cells and interleukin-17 (IL-17)-producing CD4⁺ T helper cells (T_H17 cells) are areas of intensive study. Two new reports in Nature have now identified the aryl hydrocarbon receptor (AHR) as an important ligand-dependent regulator of these reciprocal T-cell populations.

AHR is a transcription factor expressed by many cell types, but its physiological role in the immune system has not been well defined. AHR ligands include the environmental toxin TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and endogenous molecules such as FICZ (6-formylindolo[3,2-b]carbazole), a tryptophan-derived product thought to be generated in the skin following exposure to ultraviolet light. Now, studies from the Weiner and Stockinger laboratories show that AHR triggering drives either T_Reg-cell or T_H17-cell differentiation in a ligand-specific manner and, correspondingly, can protect against or promote the development of EAE (experimental autoimmune encephalomyelitis), a mouse model of multiple sclerosis.

Weiner and colleagues found that TCDD-mediated activation of AHR directly upregulated the expression of Foxp3, a gene known to be essential for T_Reg-cell function, and that T_Reg cells expressed higher levels of AHR than other T cells. Furthermore, TCDD promoted the differentiation of new antigen-specific T_Reg cells in vitro and in vivo that lessened disease severity in an induced EAE model. However, treatment of mice with the endogenous AHR ligand FICZ had the opposite effect: the differentiation of T_Reg cells was inhibited and, instead, the differentiation of T_H17 cells and the severity of EAE were increased.

Stockinger and colleagues also found that treatment of mice with FICZ promoted the effector function of differentiated T_H17 cells and worsened EAE severity. Here, AHR triggering by FICZ markedly increased IL-17 and IL-22 production by pathogenic T_H17 cells, but had no effect on induced or naturally occurring T_Reg-cell populations. In addition, T_Reg cells were not found to preferentially express AHR, as reported by Weiner and colleagues. Similar results were obtained with another ligand, beta -naphthoflavone, which, like TCDD, is an environmental toxin, but with lower affinity for AHR.

The interaction of AHR with other transcription factors, such as nuclear factor- kappa B, can influence its molecular function. In addition, AHR is known to mutually cross regulate the transforming growth factor- beta (TGF beta ) signalling pathway. Similar to AHR, TGF beta signalling can induce either T_H17-cell or T_Reg-cell differentiation, depending on the presence of other cytokines in the microenvironment. Therefore, AHR and TGF beta might be alike in their context-dependent driving of T-cell differentiation, or could synergize in promoting either T_H17 cells or T_Reg cells, depending on the nature of the immune response.

As AHR is important for cellular responses to environmental toxins such as TCDD, exposure to such agents could skew T-cell populations and influence the delicate balance between immune tolerance and autoimmunity. The finding that some AHR ligands can promote T_H17 cells opens up avenues for the development of new therapies to target these cells in vivo.

Sarah Allan

References

Quintana, F. J. et al. Control of T_reg and T_H17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008) | Article | PubMed |
Veldhoen, M. et al. The aryl hydrocarbon receptor links T_H17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008) | Article | PubMed |
Dong, C. T_H17 cells in development: an updated view of their molecular identity and genetic programming. Nature Rev. Immunol. 8, 337–348 (2008) | Article | PubMed |