JAK/STAT signaling controls the fate of CD8+CD103+ tissue-resident memory T cell in lupus nephritis
JAK/STAT signaling controls the fate of CD8+CD103+ tissue-resident memory T cell in lupus nephritis
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JAK/STAT信号控制狼疮肾炎中CD8()CD103()组织驻留记忆T细胞的命运
DOI：
10.1016/j.jaut.2020.102424
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发表时间：
2020-05-01
影响因子：
12.8
通讯作者：
Yang, Niansheng
中科院分区：
文献类型：
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作者：
Zhou, Mianjing;Guo, Chaohuan;Yang, Niansheng
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肾小球和肾间质中淋巴细胞的浸润。在这里，我们在人和小鼠的健康肾脏中鉴定出了具有 CD103(+) 表型的 CD8(+) T 细胞群。这些细胞通常是肾脏中的 CD69(+)CD103(+) 组织驻留记忆 T 细胞 (T-RM)。 CD8(+) T-RM 细胞在 LN 或 MRL/lpr 小鼠患者的肾脏中扩增。肾CD8(+) T-RM细胞的扩增与肾脏疾病活动显着相关。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-RM 细胞进行增殖和自我更新，以维持 MRL/lpr 小鼠肾脏中稳定的 T-RM 池，从而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 T-RM 自我更新以及效应器功能的维持是必需的。托法替布靶向 JAK/STAT 信号传导有效抑制效应器功能并损害肾脏中肾 T-RM 细胞的存活，有助于改善 MRL/lpr 小鼠的肾功能。这些结果证明肾脏CD8+T-RM细胞在LN的发病机制中发挥作用。它们可以作为 LN 的治疗靶点。
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 CD69(+)CD103(+) tissue-resident memory T cells (T-RM) in the kidney. CD8(+) T-RM cells were expanded in the kidneys of patients with LN or MRL/lpr mice. The expansion of renal CD8(+) T-RM 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-RM cells underwent proliferation and self-renewal to maintain a stable T-RM 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-RM 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-RM cells in the kidney, contributing to improved kidney function in MRL/lpr mice. These results provided evidences that renal CD8(+) T-RM cells play a role in the pathogenesis of LN. They could serve as a therapeutic target for LN.