The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease. J Clin Invest 2022 Nov 01;132(21)
Date
09/09/2022Pubmed ID
36074578Pubmed Central ID
PMC9621143DOI
10.1172/JCI143950Scopus ID
2-s2.0-85141004782 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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 promoted the transcription of Th1/Th17 pathways and T cell receptor-inducible (TCR-inducible) transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells. Importantly, a low dose of camptothecin, topotecan, or etoposide acted as a potent Fli-1 inhibitor and significantly attenuated GVHD severity, while preserving the graft-versus-leukemia (GVL) effect. This observation was extended to a xenograft model, in which GVHD was induced by human T cells. In conclusion, we provide evidence that Fli-1 plays a crucial role in alloreactive CD4+ T cell activation and differentiation and that targeting Fli-1 may be an attractive strategy for treating GVHD without compromising the GVL effect.
Author List
Schutt SD, Wu Y, Kharel A, Bastian D, Choi HJ, Hanief Sofi M, Mealer C, McDaniel Mims B, Nguyen H, Liu C, Helke K, Cui W, Zhang X, Ben-David Y, Yu XZAuthors
Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of WisconsinXue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Friend murine leukemia virusGraft vs Host Disease
Graft vs Leukemia Effect
Hematopoietic Stem Cell Transplantation
Humans
Leukemia
T-Lymphocytes
Transcription Factors
Transplantation, Homologous
