Sun Deming, Ko Minhee, Shao Hui, Kaplan Henry J
Doheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90033, United States.
Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY, 40202, United States.
Curr Res Immunol. 2021;2:93-103. doi: 10.1016/j.crimmu.2021.07.001. Epub 2021 Jul 26.
Various pathological conditions are accompanied by release of adenosine triphosphate (ATP) from the intracellular to the extracellular compartment, where it degrades into adenosine and modulates immune responses. Previous studies concluded that both ATP and its degradation product adenosine are important immune-regulatory molecules; ATP acted as a danger signal that promotes immune responses, but adenosine's effect was inhibitory. We show that adenosine receptor ligation plays an important role in balancing Th1 and Th17 pathogenic T cell responses in experimental autoimmune uveitis (EAU). While its effect on Th1 responses is inhibitory, its effect on Th17 responses is enhancing, thereby impacting the balance between Th1 and Th17 responses. Mechanistic studies showed that this effect is mediated via several immune cells, among which γδ T cell activation and dendritic cell differentiation are prominent; adenosine- and γδ-mediated immunoregulation synergistically impact each other's effect. Adenosine receptor ligation augments the activation of γδ T cells, which is an important promoter for Th17 responses and has a strong effect on dendritic cell (DC) differentiation, tipping the balance from generation of DCs that stimulate Th1 responses to those that stimulate Th17 responses. The knowledge acquired in this study should improve our understanding of the immune-regulatory effect of extracellular ATP-adenosine metabolism and improve treatment for autoimmune diseases caused by both Th1-and Th17-type pathogenic T cells.
多种病理状态伴随着三磷酸腺苷（ATP）从细胞内释放到细胞外间隙，在那里它降解为腺苷并调节免疫反应。先前的研究得出结论，ATP及其降解产物腺苷都是重要的免疫调节分子；ATP作为一种促进免疫反应的危险信号，而腺苷的作用则是抑制性的。我们发现，腺苷受体结合在实验性自身免疫性葡萄膜炎（EAU）中平衡Th1和Th17致病性T细胞反应方面发挥着重要作用。虽然其对Th1反应的作用是抑制性的，但其对Th17反应的作用是增强性的，从而影响Th1和Th17反应之间的平衡。机制研究表明，这种作用是通过几种免疫细胞介导的，其中γδT细胞活化和树突状细胞分化较为突出；腺苷和γδ介导的免疫调节相互协同影响彼此的作用。腺苷受体结合增强了γδT细胞的活化，γδT细胞是Th17反应的重要促进因子，对树突状细胞（DC）分化有很强的影响，使平衡从刺激Th1反应的DC生成转向刺激Th17反应的DC生成。本研究获得的知识应能增进我们对细胞外ATP - 腺苷代谢免疫调节作用的理解，并改善由Th1型和Th17型致病性T细胞引起的自身免疫性疾病的治疗。
