biostudies-literatureSchutt SDNIAID NIH HHSNational Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Allergy and Infectious Diseasese143950https://www.ebi.ac.uk/biostudies/studies/S-EPMC9621143biostudies-literatureUnknown132(21)Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 promThe Journal of clinical investigationThe druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease.PMC9621143R01 Al118305,R01 HL140953R01 AI148403Ben-David YMealer CMcDaniel Mims BChoi HJCui WKharel AHelke KHanief Sofi MBastian DNguyen HZhang XLiu CYu XZWu YSchutt SDfalseThe druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease.Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 prom2022-01-01T00:00:00Z2022 Nov2025-04-26T20:46:47.989Z2025-04-06T16:31:56.78ZS-EPMC96211433607457810.1172/JCI143950