Multimodal immune cell phenotyping in gastrointestinal biopsies reveals microbiome-related T cell modulations in human GvHD patients

Acute graft-versus-host disease (aGvHD) is a significant complication after allogeneic hematopoietic stem cell transplantation (aHSCT), but major factors determining disease severity are not well defined yet. By combining multiplexed tissue imaging and single-cell RNA sequencing on gastrointestinal biopsies from aHSCT patients with fecal microbiome analysis, we could link high microbiome diversity and the abundance of short-chain fatty acid-producing bacteria to the sustenance of suppressive regulatory T cells. Furthermore, aGvHD severity was strongly associated with the clonal expansion of mainly CD8 T cells, which we found distributed over anatomically distant regions of the gut, persistent over time, and inversely correlated with the presence of suppressive Tregs. Overall, our study highlights the pathophysiological importance of expanded CD8 T cell clones in the progression of aGvHD towards more severe clinical manifestations and strongly supports the further development of microbiome interventions as GvHD treatment via repopulation of the gut Treg niche to suppress inflammation. Overall design: scRNA sequencing data for gastrointestinal immune cells from HSCT patients

急性移植物抗宿主病（acute graft-versus-host disease, aGvHD）是异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation, aHSCT）后发生的严重并发症，但其决定疾病严重程度的核心因素尚未明确。本研究对接受aHSCT患者的胃肠道活检标本联合应用多重组织成像与单细胞RNA测序，并结合粪便微生物组分析，发现高微生物组多样性与产短链脂肪酸细菌的丰度，与抑制性调节性T细胞的维持密切相关。进一步研究显示，aGvHD的严重程度与以CD8阳性T细胞为主的克隆扩增显著相关：这类细胞分布于肠道内解剖位置相距较远的区域，且随时间持续存在，同时与抑制性调节性T细胞的丰度呈负相关。综上，本研究阐明了扩增的CD8阳性T细胞克隆在aGvHD进展为更严重临床表现过程中的病理生理重要性，并有力支持通过重建肠道Treg生态位以抑制炎症的微生物组干预手段，作为移植物抗宿主病治疗方案的进一步开发。研究整体设计：来自造血干细胞移植患者的胃肠道免疫细胞单细胞RNA测序数据。