title: The aryl hydrocarbon receptor (AhR) ligand VAF347 selectively acts on monocytes and naïve CD4(+) Th cells to promote the development of IL-22-secreting Th cells.
abstract: The low molecular weight compound VAF347, and its pro-drug version VAG539, interact with the transcription factor aryl hydrocarbon receptor (AhR) on monocytes to mediate its anti-inflammatory activity in vitro and in vivo. AhR is a crucial factor for IL-22 production, which regulates skin and gut homeostasis. Here we investigated whether VAF347 might control the differentiation of naïve T cells into IL-22-secreting cells and/or regulate IL-22 production by memory T cells. Human monocytes exposed to VAF347 differentiated into dendritic cells capable of instructing a naïve CD4(+) T cell differentiation program that promoted IL-22 secretion and concomitantly inhibited IL-17 production. Whilst AhR ligation by VAF347 on naïve CD4(+) T cells favored the development of single IL-22-secreting cells (Th22), it suppressed the generation of T cells secreting either IL-22 and IFN-γ or IL-17 and IFN-γ. In contrast, memory T cells were refractory to AhR regulation since VAF347, AhR antagonist or AhR gene silencing did not modulate the production of any of these cytokines. Interfering with AhR functions using VAF347 may provide an efficient way to intervene with autoimmune disease since it would enhance the host protective function mediated by IL-22 while preventing the development of Th cells secreting pro-inflammatory cytokines.
authors.affiliation: Immunoregulation Laboratory, Research Centre of the University of Montreal Hospital Centre, Notre-Dame Hospital (Room M4211K), 1560 Sherbrooke Street East, Montreal, Quebec, Canada H2L 4M1.
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Baba
authors.forename: Manuel
authors.initials: M
authors.lastname: Rubio
authors.forename: Linda
authors.initials: L
authors.lastname: Kenins
authors.forename: Camille
authors.initials: C
authors.lastname: Regairaz
authors.forename: Maximilian
authors.initials: M
authors.lastname: Woisetschlager
authors.forename: José M
authors.initials: JM
authors.lastname: Carballido
authors.forename: Marika
authors.initials: M
authors.lastname: Sarfati
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D011355:Prodrugs; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D000097043:Interleukin-22; C509596:VAF347