Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Surgery, Section of Transplantation, University of Chicago, Chicago, Illinois, USA.
JCI Insight. 2023 Oct 23;8(20):e169793. doi: 10.1172/jci.insight.169793.
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 cells marked by previous IL-21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNA-Seq revealed that these lymph node (LN) 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 LNs 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 LN and locally within kidney grafts. Thus, IL-21-producing effector Tfh cells have multifaceted roles in Ab-mediated rejection after kidney transplantation by promoting B cell alloimmunity.
滤泡辅助 T（Tfh）细胞已被牵涉到同种异体肾移植后的排斥反应控制中，但该过程中 Tfh 细胞的确切亚群、起源和功能尚未完全确定。在这里，我们发现一种先前由 IL-21 产生标记的效应性 Tfh 细胞亚群在同种异体肾移植过程中被强烈诱导，并被免疫抑制药物抑制。单细胞 RNA-Seq 揭示这些淋巴结（LN）效应性 Tfh 细胞与产生 IL-21 的肾浸润 Tfh 细胞在转录和克隆上重叠，提示存在共同的起源和发育轨迹。为了研究 LN 和同种异体移植物中产生 IL-21 的效应性 Tfh 细胞的确切功能，我们使用小鼠模型选择性地消除这些细胞，并使用单个 B 细胞培养系统评估同种异体 B 细胞克隆动力学。我们发现，产生 IL-21 的效应性 Tfh 细胞通过调节供体特异性生发中心 B 细胞克隆动力学在引流 LN 全身和肾移植物局部都对移植排斥反应至关重要。因此，产生 IL-21 的效应性 Tfh 细胞通过促进 B 细胞同种免疫在肾移植后的 Ab 介导排斥反应中具有多方面的作用。
