The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease
Steven D. Schutt, … , Yaacov Ben-David, Xue-Zhong Yu
Steven D. Schutt, … , Yaacov Ben-David, Xue-Zhong Yu
Published September 8, 2022
Citation Information: J Clin Invest. 2022;132(21):e143950. https://doi.org/10.1172/JCI143950.
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Research Article Immunology Transplantation

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 6

ETO and TPT prevent cGVHD.

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ETO and TPT prevent cGVHD. (A–D) cGVHD BMT was performed similarly to th...
(A–D) cGVHD BMT was performed similarly to the procedure described in Figure 4, except mice were given donor BM and splenocytes from WT-B6 mice and supplemented or not with vehicle or 5 mg/kg ETO i.p. starting on day 0 and then every other day until day 14 after BMT. The cGVHD clinical score was monitored weekly (A), and the frequencies of thymic CD4+CD8+ (B) and splenic B220+ and CD4+FoxP3+ populations (C) were determined. pLN populations of T cells producing cytokines were analyzed on approximately day 60 after BMT (D). Data are from 2 independent experiments (BM only, n = 4; BM + ETO, n = 3; BM + spleen + vehicle, n = 10; BM + spleen + ETO, n = 10). (E–G) In a similar BMT setting, the recipient mice were i.p. injected with TPT at 0.3 mg/kg every other day starting on the day of BMT for 10 days. The cGVHD clinical score was monitored weekly (E), and the absolute number of thymocytes and the frequency of thymic CD4+CD8+ (F) and splenic B220+ and CD4+Foxp3+ cells (G) were analyzed on day 60 after BMT. Cytokine production by donor CD4+ and CD8+ T cells in pLNs were analyzed on day 60 after BMT (BM only, n = 4; BM + TPT, n = 3; BM + spleen + PBS, n = 5; BM + spleen + TPT, n = 5). Significance was determined using mixed-model tests for clinical scores and 1-way ANOVA for all other data. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.