INSERM U1035, Immuno-Dermatology, Bordeaux University, Bordeaux, France.
CNRS-UMR 5164 Immuno ConcEpT, Bordeaux University, Bordeaux, France.
JCI Insight. 2018 Dec 20;3(24):122167. doi: 10.1172/jci.insight.122167.
Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell-dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.
调节性 T 细胞（Tregs）在人类系统性红斑狼疮（SLE）中受损，并促进效应 T 细胞的激活。然而，导致 SLE 中 Treg 缺陷的机制仍不清楚。我们假设 OX40L/OX40 轴参与了人类 SLE 中 Treg 和调节性滤泡辅助 T（Tfr）细胞功能障碍。OX40L/OX40 轴在 Tregs 和 Tfr 细胞上的相互作用不仅特异性地损害了它们调节效应 T 细胞增殖的能力，还损害了它们抑制滤泡辅助性 T（Tfh）细胞依赖性 B 细胞激活和免疫球蛋白分泌的能力。来自活动期 SLE 患者的抗原呈递细胞以 OX40L 依赖的方式介导 Treg 功能障碍，并且 OX40L 表达细胞与活跃的 SLE 皮肤损伤中的 Foxp3+细胞共定位。OX40L/OX40 轴的相互作用导致 Tregs 中 Foxp3 的下调，并且在 SLE Tregs 中的表达与循环中 OX40L 表达的髓样树突状细胞的比例相关。这些数据支持 OX40L/OX40 信号参与了人类 SLE 中的 Treg 功能障碍。因此，阻断 OX40L/OX40 轴似乎是一种有前途的治疗策略。
