Raverdeau Mathilde, Breen Conor J, Misiak Alicja, Mills Kingston Hg
Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Department of Biology, Maynooth University, Maynooth, Kildare, Ireland.
Immunol Cell Biol. 2016 Sep;94(8):763-73. doi: 10.1038/icb.2016.39. Epub 2016 May 10.
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.
稳态下的视黄酸（RA）可增强Foxp3(+)调节性T（Treg）细胞的诱导，并抑制Th1和Th17细胞的分化，从而维持免疫耐受，但在炎症条件下可促进介导炎症的效应性Th1和Th17细胞。最近研究表明，产生白细胞介素-17（IL-17）的γδT细胞在自身免疫性疾病中起主要致病作用。在此，我们研究了RA对γδT细胞的免疫调节作用。我们发现，RA对经IL-1β和IL-23刺激的γδT细胞产生IL-17A和IL-17F具有显著的抑制作用。RA可抑制γδT细胞中RORγt、IL-1R和IL-23R的表达。用RA处理小鼠可在体内抑制γδT细胞产生IL-17。此外，用RA处理T细胞可减弱其在实验性自身免疫性脑脊髓炎（EAE，一种多发性硬化症的小鼠模型）中诱导疾病的能力。这与中枢神经系统浸润的γδT细胞数量减少有关，同时也与产生IL-17A、IL-17F或粒细胞-巨噬细胞集落刺激因子（GM-CSF）的CD4(+)T细胞数量减少有关。有趣的是，用RA处理γδT细胞或从大量T细胞群体中去除γδT细胞可显著降低其诱导EAE的能力，这表明γδT细胞在促进致病性Th17细胞方面起关键作用。我们的研究结果表明，RA的抗炎特性部分是通过抑制γδT细胞中信号转导和转录激活因子3（STAT3）介导的细胞因子产生激活和细胞因子受体表达来实现的，这抑制了它们激活Th17细胞的能力。
