Acute GVHD in liver and lungs is mediated by phenotypically-analogous but transcriptionally unique T cells

Abstract During acute Graft-versus-Host Disease (aGVHD), donor T cells invade host tissues and cause multi-organ damage. However, the organ-specific drivers of pathogenic alloimmunity are still poorly understood. To uncover both the universal and organ-specific mechanisms driving T cell-mediated damage in target tissues during aGVHD, we analyzed the flow cytometric phenotype as well as transcriptomic signatures of T cells in healthy control animals, in autologous hematopoietic cell transplant (HCT) controls, and during aGVHD after allogeneic HCT, using our established non-human primate aGVHD model. In this study we focused on 2 aGVHD target organs: the liver and lungs. Using both supervised and unsupervised flow cytometric analysis, we discovered that, during aGVHD, both liver- and lung-infiltrating T cells demonstrated similar phenotypes dominated by mature effector-memory CD8 T cells. In contrast, transcriptomic analysis revealed organ-specific gene expression programming. Through Weighted Gene Co-expression Network Analysis (WGCNA), differential expression (DE) analysis, and immune pathway analysis, we identified that the lung aGVHD T cell transcriptomic program was specifically associated with extracellular matrix-remodeling and chemotaxis pathways. In contrast, in liver aGVHD, we found enrichment for metabolic stress responses and cytokine signaling pathways. These results suggest that at the transcriptomic level, T cells infiltrating different aGVHD-target organs are uniquely programmed and could be amenable to organ-specific therapeutic targeting. Supported by grants from the NIH (F31HL1562880)