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Identification of Cinnabarinic Acid as a Novel Endogenous Aryl Hydrocarbon Receptor Ligand That Drives Th22 Differentiation

  • Author(s): Lowe, Margaret
  • Advisor(s): McCune, Joseph M
  • et al.
Abstract

The aryl hydrocarbon receptor (AHR) is a cytosolic transcription factor that recognizes and induces metabolic enzymes in response to a wide variety of xenobiotics. However, more recently the AHR has been proven critical in a diverse array of biological processes, including organ development, circadian rhythm, and immune response. In particular, AHR activation has been shown to affect T cell differentiation for both inflammatory T cells that produce IL-17 (Th17) and IL-22 as well as regulatory T cells (Treg) involved in tolerance. Given that the balance between inflammatory and immunoregulatory T cells has been implicated in pathological processes in contexts such as HIV infection and autoimmunity, understanding the role AHR and its ligands play in immune cell diffentiation is critical. While environmental AHR ligands can alter T cell differentiation, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to alter T cell differentiation. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions.

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