title: Retinoic acid suppresses IL-17 production and pathogenic activity of γδ T cells in CNS autoimmunity.
abstract: Retinoic acid (RA) in the steady state enhances induction of Foxp3(+) regulatory T (Treg) cells and inhibits differentiation of Th1 and Th17 cells, thereby maintaining tolerance, but can in inflammatory conditions promote effector Th1 and Th17 cells that mediate inflammation. IL-17-producing γδ T cells have recently been shown to have a major pathogenic role in autoimmune diseases. Here, we examined the immunomodulatory effects of RA on γδ T cells. We found that RA had a dramatic suppressive effect on IL-17A and IL-17F production by γδ T cells stimulated with IL-1β and IL-23. RA suppressed RORγt, IL-1R and IL-23R expression in γδ T cells. Treatment of mice with RA suppressed IL-17 production by γδ T cells in vivo. Furthermore, treatment of T cells with RA attenuated their ability to induce disease in experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis. This was associated with a reduction in the number of central nervous system-infiltrating γδ T cells, but also CD4(+) T cells that produced IL-17A, IL-17F or GM-CSF. Interestingly, treatment of γδ T cells with RA or removal of γδ T cells from a bulk population of T cells significantly reduced their capacity to induce EAE, demonstrating a critical role for γδ T cells in promoting pathogenic Th17 cells. Our findings demonstrate that the anti-inflammatory properties of RA are mediated in part by suppressing STAT3-mediated activation of cytokine production and cytokine receptor expression in γδ T cells, which suppresses their ability to activate Th17 cells.
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Raverdeau
authors.affiliation: Department of Biology, Maynooth University, Maynooth, Kildare, Ireland.
authors.forename: Conor J
authors.initials: CJ
authors.lastname: Breen
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Misiak
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Kingston Hg
authors.initials: KH
authors.lastname: Mills
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D007155:Immunologic Factors / Q000494:pharmacology; D020381:Interleukin-17 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D007155:Immunologic Factors; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D063308:Myelin-Oligodendrocyte Glycoprotein; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014212:Tretinoin