Shi Lingting, Uzuni Ajna, Wang Ximi K, Pressler Michael, Harle David W, Chakrabarti Shami, Macedo Rodney, Belay Kirubel, Gordillo Christian A, Raps Erik, Zhang Jia Yi Ady, Nazaret Achille, Fan Joy L, Jin Yinuo, Shen Xumin, Fuller Joshua S, Azad Tamjeed, Huang Jessie, Chainani Pranik, Abrams Julian A, Del Portillo Armando, Mapara Markus Y, Alhamar Mohamed, Sykes Megan, McFaline-Figueroa José L, Azizi Elham, Reshef Ran
Irving Institute for Cancer Dynamics, Columbia University, New York, NY, 10027, USA.
Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.
bioRxiv. 2025 May 28:2025.05.24.655962. doi: 10.1101/2025.05.24.655962.
Allogeneic hematopoietic cell transplantation (alloHCT) is curative for various hematologic diseases but often leads to acute graft-versus-host disease (GVHD), a potentially life-threatening complication. We leverage GVHD as a uniquely tractable disease model to dissect complex T-cell-mediated pathology in 27 alloHCT recipients. We integrate pre-transplant identification of alloreactive T-cells with longitudinal tracking across blood and gut, using mixed lymphocyte reaction-based clonal "fingerprinting", TCR clonotyping, single-cell RNA/TCR sequencing, and spatial transcriptomics. Using DecompTCR, a novel computational tool for longitudinal TCR analysis, we uncover clonal expansion programs linked to GVHD severity and TCR features. Multi-omics profiling of gut biopsies reveals enrichment and clonal expansion of CD8 effector and ZNF683(Hobit) resident memory T-cells, cytolytic remodeling of regulatory and unconventional T-cells, and localization of CD8 effector T-cells near intestinal stem cells in crypt loss regions. This framework defines dynamic immune circuit rewiring and phenotypic plasticity with implications for biomarkers and therapies.
异基因造血细胞移植（alloHCT）可治愈多种血液疾病，但常常会引发急性移植物抗宿主病（GVHD），这是一种可能危及生命的并发症。我们利用GVHD作为一种独特的易于处理的疾病模型，剖析了27例alloHCT受者中复杂的T细胞介导的病理过程。我们使用基于混合淋巴细胞反应的克隆“指纹识别”、TCR克隆分型、单细胞RNA/TCR测序和空间转录组学，将移植前对同种反应性T细胞的鉴定与跨血液和肠道的纵向追踪相结合。使用DecompTCR（一种用于纵向TCR分析的新型计算工具），我们发现了与GVHD严重程度和TCR特征相关的克隆扩增程序。肠道活检的多组学分析揭示了CD8效应T细胞和ZNF683（Hobit）组织驻留记忆T细胞的富集和克隆扩增、调节性和非常规T细胞的溶细胞重塑，以及CD8效应T细胞在隐窝丢失区域的肠道干细胞附近的定位。该框架定义了动态免疫回路重塑和表型可塑性，对生物标志物和治疗具有重要意义。
