Organ-specific microenvironments drive divergent T cell evolution in acute Graft-Versus-Host Disease 3176

Abstract Description Tissue-specific T cell immune responses play a critical role in maintaining organ health, but can also drive immune pathology during both auto- and alloimmunity. The mechanisms controlling intra-tissue T cell programming remain unclear. Here, we leverage a non-human primate model of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT) to probe the biological underpinnings of tissue-specific aGVHD, using a comprehensive systems immunology approach. Transcriptional profiling revealed substantial biological differences between T cells infiltrating the lung and liver during aGVHD. These included enrichment for pathways controlling chemotaxis and extracellular matrix remodeling in the lung, and enrichment for pathways linked to nucleic acid metabolism and proliferation in the liver. Single cell RNA- and TCR-sequencing substantiated divergent organ-specific transcriptional programing of tissue-infiltrating T cells, which was linked to clonal expansion. This divergent evolution of T cells was maintained even for T cells sharing the same TCRs, indicating its independence from antigen-specificity. Together, these results provide new insights into the principal role that tissue microenvironment-derived signals play in local T cell transcriptional programming during alloimmune-mediated clonal expansion, and which suggest potential opportunities to develop tissue-specific therapeutics to curtail pathogenic immunity after transplant. Funding Sources NIH R01 HL095791; NIH P01 HL158504; NIH U19 AI051731; NIH R01 HL095791; NIH R01 HL115114; NIH R37 AI34495; NIH U19 AI174967; NIH F31 HL156288; NIH T32 HL116275; ASTCT Investigator Award; Be the Match Foundation/CIBMTR Amy Strelzer Manasevit Research Grant; American Society of Transplantation Early Faculty Development Research Grant Topic Categories Transplantation Immunology (TRAN)