Louis Kevin, Tabib Tracy, Macedo Camila, Wang Jiefei, Cantalupo Paul, Chandran Uma, Gu Xinyan, Lucas Michelle, Randhawa Parmjeet, Abundis Marisa, Das Jishnu, Singh Harinder, Lefaucheur Carmen, Metes Diana
Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Human Immunology and Immunopathology, Inserm UMR 976, Université Paris Cité, Paris, France.
Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Am J Transplant. 2025 Apr;25(4):706-719. doi: 10.1016/j.ajt.2024.10.009. Epub 2024 Oct 16.
Rejection is a primary cause of allograft dysfunction after kidney transplantation. The diversity of immune subpopulations involved in the different endotypes of rejection remains to be delineated at single-cell resolution. In a cohort of 76 kidney transplant recipients, we conducted high-dimensional immune phenotyping of blood CD4 T and B cells, single-cell RNA and T/B cell receptor sequencing, and plasma cytokine profiling. Phenotypic, transcriptional, and clonal states of CD4T and B cells could significantly distinguish stable allograft states from rejection. Patients undergoing T cell-mediated rejection displayed accumulation of clonally expanded cytotoxic T helper (Th)1 cells and Th17-like cells, associated with predominant naive B cell responses. In contrast, antibody-mediated rejection was characterized by clonal expansion of Th1-polarized T follicular helper cells and effector T-bet+ memory B cells, both of which strongly expressed interleukin 12 and tumor necrosis factor-signaling pathways. Plasma cytokine analysis confirmed mixed Th1/Th17 and Th1/T follicular helper cell-driven inflammatory profiles distinguishing T cell-mediated rejection and antibody-mediated rejection, respectively. CD4T and B cell subpopulations and signatures were validated using bulk RNA-seq analysis of matched kidney allografts and using an independent single-cell RNA-seq data set. These data improve mechanistic understanding of the immune pathogenesis of rejection and support the development of more specific immunosuppressive therapies to treat allograft rejection.
排斥反应是肾移植后同种异体移植功能障碍的主要原因。参与不同排斥反应亚型的免疫亚群的多样性仍有待在单细胞分辨率下进行描绘。在一组76名肾移植受者中，我们对血液中的CD4 T细胞和B细胞进行了高维免疫表型分析、单细胞RNA和T/B细胞受体测序以及血浆细胞因子分析。CD4 T细胞和B细胞的表型、转录和克隆状态能够显著区分稳定的同种异体移植状态和排斥反应。经历T细胞介导排斥反应的患者表现出克隆性扩增的细胞毒性T辅助（Th）1细胞和Th17样细胞的积累，这与主要的幼稚B细胞反应相关。相比之下，抗体介导的排斥反应的特征是Th1极化的滤泡辅助性T细胞和效应性T-bet+记忆B细胞的克隆性扩增，这两种细胞均强烈表达白细胞介素12和肿瘤坏死因子信号通路。血浆细胞因子分析证实了分别区分T细胞介导排斥反应和抗体介导排斥反应的混合Th1/Th17和Th1/滤泡辅助性T细胞驱动的炎症谱。使用匹配的肾同种异体移植的批量RNA测序分析以及独立的单细胞RNA测序数据集对CD4 T细胞和B细胞亚群及特征进行了验证。这些数据提高了对排斥反应免疫发病机制的机制理解，并支持开发更具特异性的免疫抑制疗法来治疗同种异体移植排斥反应。
