Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Am Soc Nephrol. 2023 Jun 1;34(6):1003-1018. doi: 10.1681/ASN.0000000000000116. Epub 2023 Mar 13.
T-cell infiltration is a hallmark of crescentic GN (cGN), often caused by ANCA-associated vasculitis. Pathogenic T-cell subsets, their clonality, and downstream effector mechanisms leading to kidney injury remain to be fully elucidated. Single-cell RNA sequencing and T-cell receptor sequencing revealed activated, clonally expanded cytotoxic CD4 + and CD8 + T cells in kidneys from patients with ANCA-associated cGN. In experimental cGN, kidney-infiltrating CD8 + T cells expressed the cytotoxic molecule, granzyme B (GzmB), which induced apoptosis in renal tissue cells by activation of procaspase-3, and aggravated disease pathology. These findings describe a pathogenic function of (clonally expanded) cytotoxic T cells in cGN and identify GzmB as a mediator and potential therapeutic target in immune-mediated kidney disease.
Crescentic GN (cGN) is an aggressive form of immune-mediated kidney disease that is an important cause of end stage renal failure. Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis is a common cause. T cells infiltrate the kidney in cGN, but their precise role in autoimmunity is not known.
Combined single-cell RNA sequencing and single-cell T-cell receptor sequencing were conducted on CD3 + T cells isolated from renal biopsies and blood of patients with ANCA-associated cGN and from kidneys of mice with experimental cGN. Functional and histopathological analyses were performed with Cd8a-/- and GzmB-/- mice.
Single-cell analyses identified activated, clonally expanded CD8 + and CD4 + T cells with a cytotoxic gene expression profile in the kidneys of patients with ANCA-associated cGN. Clonally expanded CD8 + T cells expressed the cytotoxic molecule, granzyme B (GzmB), in the mouse model of cGN. Deficiency of CD8 + T cells or GzmB ameliorated the course of cGN. CD8 + T cells promoted macrophage infiltration and GzmB activated procaspase-3 in renal tissue cells, thereby increasing kidney injury.
Clonally expanded cytotoxic T cells have a pathogenic function in immune-mediated kidney disease.
T 细胞浸润是新月体性肾小球肾炎 (cGN) 的一个标志，通常由 ANCA 相关性血管炎引起。致病 T 细胞亚群、其克隆性以及导致肾脏损伤的下游效应机制仍有待充分阐明。单细胞 RNA 测序和 T 细胞受体测序显示，在 ANCA 相关性 cGN 患者的肾脏中存在激活的、克隆扩增的细胞毒性 CD4+和 CD8+T 细胞。在实验性 cGN 中，肾浸润的 CD8+T 细胞表达细胞毒性分子颗粒酶 B（GzmB），通过激活半胱天冬酶-3 诱导肾组织细胞凋亡，并加重疾病病理。这些发现描述了 cGN 中（克隆扩增的）细胞毒性 T 细胞的致病功能，并确定 GzmB 是免疫介导的肾脏疾病的一种介质和潜在治疗靶点。
新月体性肾小球肾炎 (cGN) 是一种侵袭性免疫介导的肾脏疾病，是终末期肾衰竭的重要原因。抗中性粒细胞胞质抗体 (ANCA) 相关性血管炎是常见病因。T 细胞浸润在 cGN 中，但它们在自身免疫中的确切作用尚不清楚。
对 ANCA 相关性 cGN 患者的肾活检和血液以及实验性 cGN 小鼠的肾脏中分离的 CD3+T 细胞进行了单细胞 RNA 测序和单细胞 T 细胞受体测序。使用 Cd8a-/-和 GzmB-/-小鼠进行功能和组织病理学分析。
单细胞分析鉴定出在 ANCA 相关性 cGN 患者的肾脏中存在激活的、克隆扩增的 CD8+和 CD4+T 细胞，具有细胞毒性基因表达谱。在 cGN 的小鼠模型中，克隆扩增的 CD8+T 细胞表达细胞毒性分子颗粒酶 B（GzmB）。CD8+T 细胞缺失或 GzmB 缺乏可改善 cGN 的病程。CD8+T 细胞促进巨噬细胞浸润，GzmB 激活肾组织细胞中的半胱天冬酶-3，从而增加肾脏损伤。
克隆扩增的细胞毒性 T 细胞在免疫介导的肾脏疾病中具有致病作用。
