Zhou Mianjing, Guo Chaohuan, Li Xue, Huang Yuefang, Li Mengyuan, Zhang Tengyue, Zhao Siyuan, Wang Shuang, Zhang Hui, Yang Niansheng
Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
J Autoimmun. 2020 May;109:102424. doi: 10.1016/j.jaut.2020.102424. Epub 2020 Feb 19.
Autoimmune mediated inflammation and renal damage in lupus nephritis (LN) depends partly on the infiltration of lymphocytes in glomeruli and renal interstitium. Here we identified a population of CD8 T cells with a CD103-phenotype in the healthy kidneys of human and mouse. These cells were typically CD69CD103 tissue-resident memory T cells (T) in the kidney. CD8 T cells were expanded in the kidneys of patients with LN or MRL/lpr mice. The expansion of renal CD8 T cells correlated significantly with kidney disease activity. These cells were active in producing cytokines, perforin and granzyme B in the kidney of MRL/lpr mice. Importantly, renal CD8 T cells underwent proliferation and self-renewal to maintain a stable T pool in the kidney of MRL/lpr mice, contributing to renal inflammation and damage. JAK/STAT signaling in the MRL/lpr mice was required for renal T self-renewal as well as maintenance of effector functions. Targeting JAK/STAT signaling by tofacitinib effectively suppressed effector functions and impaired the survival of renal T cells in the kidney, contributing to improved kidney function in MRL/lpr mice. These results provided evidences that renal CD8 T cells play a role in the pathogenesis of LN. They could serve as a therapeutic target for LN.
狼疮性肾炎（LN）中自身免疫介导的炎症和肾损伤部分取决于淋巴细胞在肾小球和肾间质中的浸润。在此，我们在人和小鼠的健康肾脏中鉴定出一群具有CD103表型的CD8 T细胞。这些细胞在肾脏中通常是CD69⁺CD103⁺组织驻留记忆T细胞（TRM）。CD8 T细胞在LN患者的肾脏或MRL/lpr小鼠中扩增。肾脏CD8 T细胞的扩增与肾脏疾病活动显著相关。这些细胞在MRL/lpr小鼠的肾脏中活跃地产生细胞因子、穿孔素和颗粒酶B。重要的是，肾脏CD8 T细胞在MRL/lpr小鼠的肾脏中进行增殖和自我更新以维持稳定的TRM库，导致肾脏炎症和损伤。MRL/lpr小鼠中的JAK/STAT信号传导对于肾脏TRM的自我更新以及效应器功能的维持是必需的。用托法替布靶向JAK/STAT信号传导可有效抑制效应器功能并损害肾脏中肾脏TRM的存活，从而改善MRL/lpr小鼠的肾功能。这些结果证明肾脏CD8 T细胞在LN的发病机制中起作用。它们可作为LN的治疗靶点。
