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

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

  • Mol Ther. 2022 Aug 3;30(8):2746-2759. doi: 10.1016/j.ymthe.2022.04.024.
Liang Li 1,  Wei Tang 2,  Yan Zhang 1,  Meng Jia 1,  Limei Wang 3,  Quanxin Li 1,  Qingsheng Han 1,  Xiuping Peng 1,  Yusheng Xie 1,  Jichao Wu 1,  Ziying Wang 1,  Junhui Zhen 4,  Xiaojie Wang 1,  Min Liu 1,  Yu Sun 1,  Chun Zhang 5,  Fan Yi 6
Affiliations

Affiliations

  • 1 The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China.
  • 2 Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
  • 3 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 4 Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
  • 5 Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 6 The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China. Electronic address: fanyi@sdu.edu.cn.
PMID: 35514086 DOI: 10.1016/j.ymthe.2022.04.024
Abstract

Although tissue-resident-memory T (TRM) 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 TRM 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+ TRM 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+ TRM 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 TRM 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+ TRM cell fates. Collectively, our studies provide direct evidence for the pivotal role of renal CD8+ TRM cells in podocyte injury and further strengthen that targeting TRM cells represents a novel therapeutic strategy for patients with glomerular diseases.

Keywords

FSGS; IL-15; Sparsentan; T(RM) cells; diabetes; podocyte injury.

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