IL-21 Producing Effector Tfh Cells Promote B Cell Alloimmunity in Lymph Nodes and Kidney Allografts. IL-21 Producing Effector Tfh Cells Promote B Cell Alloimmunity in Lymph Nodes and Kidney Allografts

Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins and functions of Tfh cells in this process have not been fully characterized. Here we show that a subset of effector Tfh cell marked by previous IL- 21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNAseq revealed that these lymph node effector Tfh cells have transcriptional and clonal overlap with IL-21 producing kidney infiltrating Tfh cells, implicating common origins and developmental trajectories. To investigate the precise functions of IL-21 producing effector Tfh cells in lymph nodes and allografts, we used a mouse model to selectively eliminate these cells and assessed allogeneic B cell clonal dynamics using a single B cell culture system. We found that IL-21 producing effector Tfh cells were essential for transplant rejection by regulating donor-specific germinal center B cell clonal dynamics both systemically in the draining lymph node and locally within kidney grafts. Thus, IL-21 producing effector Tfh cells have multifaceted roles in antibody-mediated rejection after kidney transplantation by promoting B cell alloimmunity. Overall design: Lymph node and graft T follicular helper cells and lymph node Tcon all in duplicate

滤泡辅助性T细胞（Follicular helper T, Tfh）已被证实参与同种异体肾移植术后的排斥反应调控，但此类细胞在该过程中的确切亚群、起源及功能尚未得到完全阐明。本研究发现，在同种异体肾移植过程中，一类以既往产生IL-21为特征的效应性Tfh细胞亚群被强力诱导，且可被免疫抑制剂抑制。单细胞RNA测序（Single-cell RNAseq）结果显示，这些淋巴结中的效应性Tfh细胞与浸润于肾脏的产IL-21 Tfh细胞存在转录组与克隆型重叠，提示二者具有共同的起源与发育轨迹。为探究淋巴结与移植物中产IL-21的效应性Tfh细胞的确切功能，本研究采用小鼠模型选择性清除此类细胞，并通过单细胞B细胞培养体系评估同种异体B细胞的克隆动态变化。研究结果显示，产IL-21的效应性Tfh细胞可通过调控引流淋巴结系统内及肾移植物局部的供体特异性生发中心B细胞克隆动态变化，从而在移植排斥反应中发挥关键作用。综上，产IL-21的效应性Tfh细胞通过促进B细胞同种免疫，在肾移植术后抗体介导的排斥反应中发挥多维度调控作用。实验设计概述：淋巴结与移植物中的滤泡辅助性T细胞，以及淋巴结中的常规T细胞（T conventional, Tcon），均设置双重复样本。