An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis.

Abstract

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) participates in the differentiation of FoxP3(+) T(reg), Tr1 cells, and IL-17-producing T cells (Th17). Most of our understanding on the role of AHR on the FoxP3(+) T(reg) compartment results from studies using the toxic synthetic chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin. Thus, the physiological relevance of AHR signaling on FoxP3(+) T(reg) in vivo is unclear. We studied mice that carry a GFP reporter in the endogenous foxp3 locus and a mutated AHR protein with reduced affinity for its ligands, and found that AHR signaling participates in the differentiation of FoxP3(+) T(reg) in vivo. Moreover, we found that treatment with the endogenous AHR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) given parenterally or orally induces FoxP3(+) T(reg) that suppress experimental autoimmune encephalomyelitis. ITE acts not only on T cells, but also directly on dendritic cells to induce tolerogenic dendritic cells that support FoxP3(+) T(reg) differentiation in a retinoic acid-dependent manner. Thus, our work demonstrates that the endogenous AHR ligand ITE promotes the induction of active immunologic tolerance by direct effects on dendritic and T cells, and identifies nontoxic endogenous AHR ligands as potential unique compounds for the treatment of autoimmune disorders.

• Authors: Francisco J Quintana, Gopal Murugaiyan, Mauricio F Farez, Meike Mitsdoerffer, Ann-Marcia Tukpah, Evan J Burns, Howard L Weiner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 48 Pg. 20768-73 (Nov 30 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 21068375 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Indoles
• Ligands
• Receptors, Aryl Hydrocarbon
• Thiazoles
• Tretinoin

Topics

• Adoptive Transfer
• Animals
• Cell Compartmentation (drug effects)
• Cell Differentiation (drug effects)
• Dendritic Cells (cytology, drug effects, immunology)
• Encephalomyelitis, Autoimmune, Experimental (immunology, prevention & control)
• Forkhead Transcription Factors (metabolism)
• Immune Tolerance (drug effects)
• Indoles (metabolism)
• Ligands
• Mice
• Mice, Inbred C57BL
• Receptors, Aryl Hydrocarbon (metabolism)
• T-Lymphocytes, Regulatory (cytology, drug effects, immunology)
• Thiazoles (metabolism)
• Tretinoin (pharmacology)