AHR Function in Lymphocytes: Emerging Concepts

Abstract

The aryl hydrocarbon receptor (AHR) is an important regulator of the development and function of both innate and adaptive immune cells through roles associated with AHR's ability to respond to cellular and dietary ligands. Recent findings have revealed tissue and context-specific functions for AHR in both homeostasis and in during an immune response. I review these findings here, and integrate them into the current understanding of the mechanisms that regulate AHR transcription and function. I propose a conceptual framework in which AHR function is determined by three factors: the amount of AHR in any given cell, the abundance and potency of AHR ligands within certain tissues, and the tissue microenvironment wherein AHR(+) cells reside. This complexity emphasizes the necessity cell-type specific genetic approaches towards the study of AHR function.

Figure 1

Control of mucosal immunity by Ahr at the interface between the host and external environment. The gut is enriched with metabolites derived from either food or microflora, and some of these metabolites can function as Ahr ligands, binding to Ahr to induce its nuclear translocation and transcriptional activiation. The gut also has a cytokine mileau resulting from the cytokine production by immune cells such as dendritic cells, likely in response to gut microbiota. These environmental cues instruct the differentiation programs of immune cells (such as innate lymphoid cells and T cells), promoting the secretion of IL-22, which activates gut epithelial cells to produce antimicrobial peptides that control bacterial infections.

Figure 2

The structure and transcriptional activation of Ahr. (A) Functional domains of Ahr. bHLH (basic helix – loop – helix); PAS (Per – Arnt – Sim) domain containing PAS A and B repeats; Q-rich (glutamine rich) region; the location of functional domains are indicated by double arrows. (B) Transcriptional activation of Ahr. Ligands diffuse into the cell and are bound by the cytosolic Ahr complex. The ligand-bound receptor complex translocates into the nucleus and heterodimerizes with ARNT. Ahr-ARNT complex binds to AhRE, leading to transcriptional activation of target genes.

Figure 3

Cooperativity between Ahr and RORγt in the Il22 transcriptional regulation. RORγt and Ahr may act synergistically to enhance the Il22 transcription, and this synergy may result from multiple molecular interactions. The interaction between Ahr and RORγt is depicted at the Il22 promoter. Similar synergy could be present at the intron 1 of the Il22, where AhRE and RORE cluster.

Figure 4

Ahr⁺ Treg cells in immune homeostasis. Treg cells may respone to Ahr ligands present in the local tissue milieu, and pathways triggered downstream of this response may be relevant for the maintenance of immune homeostasis via the regulation of both adaptive (Th1/Th17) and innate (dendritic cell (DC) or macrophage (MΦ)) responses.