The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease
Steven D. Schutt, Yongxia Wu, Arjun Kharel, David Bastian, Hee-Jin Choi, Mohammed Hanief Sofi, Corey Mealer, Brianyell McDaniel Mims, Hung Nguyen, Chen Liu, Kris Helke, Weiguo Cui, Xian Zhang, Yaacov Ben-David, Xue-Zhong Yu
Steven D. Schutt, Yongxia Wu, Arjun Kharel, David Bastian, Hee-Jin Choi, Mohammed Hanief Sofi, Corey Mealer, Brianyell McDaniel Mims, Hung Nguyen, Chen Liu, Kris Helke, Weiguo Cui, Xian Zhang, Yaacov Ben-David, Xue-Zhong Yu
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Research Article Immunology

The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease

Abstract

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.

Authors

Steven D. Schutt, Yongxia Wu, Arjun Kharel, David Bastian, Hee-Jin Choi, Mohammed Hanief Sofi, Corey Mealer, Brianyell McDaniel Mims, Hung Nguyen, Chen Liu, Kris Helke, Weiguo Cui, Xian Zhang, Yaacov Ben-David, Xue-Zhong Yu

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Figure 9

CPT inhibits human Fli-1 and reduces GVHD in a xenograft model.

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CPT inhibits human Fli-1 and reduces GVHD in a xenograft model. HLA-A2+ ...
HLA-A2+ NSG mice were sublethally irradiated (250 cGy) and transplanted with 8 × 106 to 10 × 106 total human PBMCs from a healthy donor (HLA-A2–) to induce human GVHD. These mice received vehicle or CPT at 0.25–0.5 mg/kg on day 0, which was then every other day until day 14 after BMT. Recipient survival rates (A) and body weights (B) were monitored up to 80 days after transplantation. Peripheral blood staining of human (Hu) CD8+ T cells on day 14 after transplantation (C). Staining of human T cells within spleens of xenograph recipients on day 15 after transplantation (D), and percentage and number of human IFN-γ–producing CD3+CD8– T cells (top) and human IFN-γ–producing CD3+CD8+ T cells (bottom) (E). Western blot of day-15 splenic whole-cell lysates from 4 vehicle-treated and 4 CPT-treated xenografted mice using the indicated primary antibodies (F). Data in A and B represent 2 independent experiments (IRR only, n = 6; IRR + PBMCs + vehicle, n = 10; IRR + PBMCs + CPT, n = 10). Data in C–F were collected from 1 set of mice belonging to 2 independent experiments. Significance was determined using mixed-model tests for body weight, a log-rank test for survival data, and an unpaired, 2-tailed Student’s t test for all other data. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. IRR, irradiation.