AHR-mediated immunomodulation: the role of altered gene transcription

Abstract

The immune system is a sensitive target for aryl hydrocarbon receptor (AHR)-mediated transcriptional regulation. Most of the cells that participate in immune responses express AHR protein, and many genes involved in their responses contain multiple DRE sequences in their promoters. However, the potential involvement of many of these candidate genes in AHR-mediated immunomodulation has never been investigated. Many obstacles to understanding the transcriptional effects of AHR activation exist, owing to the complexities of pathogen-driven inflammatory and adaptive immune responses, and to the fact that activation of AHR often influences the expression of genes that are already being regulated by other transcriptional events in responding cells. Studies with TCDD as the most potent, non-metabolized AHR ligand indicate that AHR activation alters many inflammatory signals that shape the adaptive immune response, contributing to altered differentiation of antigen-specific CD4(+) T helper (TH) cells and altered adaptive immune responses. With TCDD, most adaptive immune responses are highly suppressed, which has been recently linked to the AHR-dependent induction of CD4(+)CD25(+) regulatory T cells. However activation of AHR by certain non-TCDD ligands may result in other immune outcomes, as a result of metabolism of the ligand to active metabolites or to unknown ligand-specific effects on AHR-mediated gene transcription. Based on studies using AHR(-/-) mice, evidence for a role of endogenous AHR ligands in regulation of the immune response is growing, with bilirubin and lipoxinA4 representing two promising candidates.

Figure 1

Cellular interactions between pathogen-activated dendritic cells (DCs) and CD4⁺ T cells, along with cytokines produced by cells of the innate immune response, determine the outcome of T cell differentiation and the type of adaptive immune response that develops. AHR is expressed in both DCs and in CD4⁺ T cells, and changes in both types of cells have been described following exposure to TCDD (refer to text for details).

Figure 2

T cell differentiation proceeds along distinct pathways following antigen presentation by DCs. Depending on the cytokines that are produced by the DC during naïve T cell activation, expression of specific transcription factors are upregulated that control T cell differentiation. Other pathways of T cell differentiation are counter-regulated by the presence of cytokines that drive a specific pathway. This assures the development of immune responses that are optimized for clearing the infectious agent that initiated the response. Inducible regulatory T cells (iTreg) develop under conditions where the cytokines that drive other pathways are not produced or co-stimulation by DCs is deficient. The iTreg pathway is enhanced by exposure of CD4⁺ T cells to TCDD (49,50)