Chevalier Nina, Thorburn Alison N, Macia Laurence, Tan Jian, Juglair Laurent, Yagita Hideo, Yu Di, Hansbro Philip M, Mackay Charles R
Department of Rheumatology and Clinical Immunology, University Medical Centre Freiburg, 79106 Freiburg, Germany; Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia; Immunology Department, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia;
Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia;
J Immunol. 2014 Nov 15;193(10):4845-58. doi: 10.4049/jimmunol.1302966. Epub 2014 Oct 22.
The dynamic interplay between regulatory T cells (T(regs)) and effector T cells (T(effs)) governs the balance between tolerance and effector immune responses. Perturbations of T(reg) frequency and function or imbalances in T(reg)/T(eff) levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. T(regs) displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to T(effs) (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient T(reg) control of T(effs) and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic T(reg) production and recruitment to inflamed tissues was too slow for disease prevention. Increased T(eff) over T(reg) expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that T(reg) expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of T(effs). Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers T(reg) proliferation, whereas exaggerated IL-21 levels overwhelm T(reg) control by supporting T(eff) expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.
调节性T细胞（Tregs）与效应性T细胞（Teffs）之间的动态相互作用决定了免疫耐受与效应免疫反应之间的平衡。Treg频率和功能的紊乱或Treg/Teff水平的失衡与自身免疫性疾病的发生有关。介导这些变化的因素仍知之甚少，本研究在小鼠自身免疫性关节炎中对其进行了探究。在患关节炎的小鼠中，Tregs表现出稳定的表型，并且在体外抑制试验中功能完全正常。然而，在自身免疫反应的早期阶段，相对于Teffs（T滤泡辅助细胞和Th17细胞），它们的扩增有所延迟。这种失衡可能导致Tregs对Teffs的控制不足并诱发自身免疫。此外，胸腺Treg产生的反调节性增加以及向炎症组织的募集可能由IL-7驱动，但对于疾病预防来说速度过慢。炎症和淋巴细胞减少进一步加剧了Teff相对于Treg扩增的增加。这两种情况都促成了自身免疫发病机制，并且伴随着IL-2可用性的降低和IL-21水平的升高。使用IL-2中和或补充来表明Treg扩增主要依赖于这种细胞因子。使用IL-21R（-/-）细胞来证明IL-21促进了Teffs的维持。因此，在实验性关节炎的炎症部位，IL-2的缺乏阻碍了Treg增殖，而过高的IL-21水平通过支持Teff扩增而使Treg的控制失效。这确定了IL-2和IL-21是自身免疫治疗中可操控的靶点。
