Injured epithelial cell states impact kidney allograft survival after T-cell-mediated rejection

作者：Anna Maria Pfefferkorn, Lorenz Jahn, Patrick T. Gauthier, Vera A. Kulow, Johannes Roeles, Niklas Müller-Bötticher, Louisa M. S. Gerhardt, Janna Leiz, Sadia Sarfraz, Izabela Plumbom, Robert Greite, S. Lovric, Jaba Gamrekelashvili, Florian P. Limbourg, Jessica Schmitz, Jan Hinrich Bräsen, Irina Scheffner, Sauer Igor, Felix Aigner, Altmüller, Janine, Thomas Conrad, Wilfried Gwinner, Naveed Ishaque, Michael Fähling, Kai M. Schmidt-Ott, Philip F. Halloran, Muhammad Ashraf, Christian Hinze · 发表于：Refubium (Universitätsbibliothek der Freien Universität Berlin) · 年份：2026 · DOI：10.17169/refubium-51247 · 研究领域：Single-cell and spatial transcriptomics、Renal Transplantation Outcomes and Treatments、Cytomegalovirus and herpesvirus research

T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure, despite being considered treatable. Its impact reflects a limited understanding of the underlying molecular mechanisms and their clinical consequences. To address this, we induced acute TCMR in mouse kidney transplants and profiled molecular changes using single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics and immunofluorescence. Results were compared with human snRNA-seq data from TCMR and stable allografts, as well as single-cell deconvolution analysis of bulk transcriptomic data from kidney transplant biopsies. Here we show that TCMR induces injured epithelial cell states in mouse kidney allografts, particularly in proximal tubules and thick ascending limbs. Spatial transcriptomics of these injured epithelial states demonstrated heterogeneous localization, interactions with immune cells and cellular microenvironments. Cross-species analysis confirmed similar severely injured epithelial states in human samples, whose abundances correlated with transplant survival and persisted despite TCMR resolution. Collectively, our results identify epithelial injury cell states as a determinant of outcome after TCMR.