Retinoic acid suppresses IL-17 production and pathogenic activity of [gamma][delta] T cells in CNS autoimmunity

• Published in: Immunology and cell biology Vol. 94; no. 8; p. 763
• Main Authors: Raverdeau, Mathilde, Breen, Conor J, Misiak, Alicja, Mills, Kingston Hg
• Format: Journal Article
• Language: English
• Published: London Blackwell Science Ltd 01.09.2016
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2016.39

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.