Targeting tissue-resident memory CD8+ T cells in the kidney is a potential therapeutic strategy to ameliorate podocyte injury and glomerulosclerosis

作者：Liang Li, Wei Tang, Yan Zhang, Meng Jia, Limei Wang, Quanxin Li, Qingsheng Han, Xiuping Peng, Yusheng Xie, Jichao Wu, Ziying Wang, Junhui Zhen, Xiaojie Wang, Min Liu, Yu Sun, Chun Zhang, Fan Yi · 发表于：Molecular Therapy · 年份：2022 · DOI：10.1016/j.ymthe.2022.04.024 · 被引用次数：63 · 研究领域：Renal Diseases and Glomerulopathies、T-cell and B-cell Immunology、Complement system in diseases

Although tissue-resident-memory T (T RM ) cells, a recently identified non-circulating memory T cell population, play a crucial role in mediating local immune responses and protect against pathogens upon local reinfection, the composition, effector function, and specificity of T RM cells in the kidney and their relevance for chronic kidney disease remain unknown. In this study, we found that renal tissue displayed high abundance of tissue-resident lymphocytes, and the proportion of CD8 + T RM cells was significantly increased in the kidney from patients and mice with focal segmental glomerulosclerosis (FSGS), diabetic kidney disease (DKD), and lupus nephritis (LN). Mechanistically, IL-15 significantly promoted CD8 + T RM cell formation and activation, thereby promoting podocyte injury and glomerulosclerosis. Interestingly, Sparsentan, the dual angiotensin II (Ang II) receptor and endothelin type A receptor antagonist, can also reduce T RM cell responses by intervening IL-15 signaling, exploring its new pharmacological functions. Mechanistically, Sparsentan inhibited Ang II or endothelin-1 (ET-1)-mediated IL-15 signaling, thereby further regulating renal CD8 + T RM cell fates. Collectively, our studies provide direct evidence for the pivotal role of renal CD8 + T RM cells in podocyte injury and further strengthen that targeting T RM cells represents a novel therapeutic strategy for patients with glomerular diseases.