An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis.
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.
Center for Neurologic Diseases, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. fquintana@rics.bwh.harvard.edu
Francisco J
FJ
Quintana
Gopal
G
Murugaiyan
Mauricio F
MF
Farez
Meike
M
Mitsdoerffer
Ann-Marcia
AM
Tukpah
Evan J
EJ
Burns
Howard L
HL
Weiner
D019264:Adoptive Transfer; D000818:Animals; D002451:Cell Compartmentation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects; D007211:Indoles / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D013844:Thiazoles / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
C548651:2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007211:Indoles; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D013844:Thiazoles; D014212:Tretinoin