Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity
Qinjian Li, … , Xi Zhang, Defu Zeng
Qinjian Li, … , Xi Zhang, Defu Zeng
Published August 1, 2023
Citation Information: J Clin Invest. 2023;133(15):e165723. https://doi.org/10.1172/JCI165723.
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Research Article Hematology

Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity

Abstract

STAT3 deficiency (STAT3–/–) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3–/– donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose–dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling–mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects.

Authors

Qinjian Li, Xiaoqi Wang, Qingxiao Song, Shijie Yang, Xiwei Wu, Dongyun Yang, Isabelle J. Marié, Hanjun Qin, Moqian Zheng, Ubaydah Nasri, Xiaohui Kong, Bixin Wang, Elizabeth Lizhar, Kaniel Cassady, Josh Tompkins, David Levy, Paul J. Martin, Xi Zhang, Defu Zeng

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Figure 10

Degradation of STAT3 in donor T cells prevents acute GVHD in a PD-1–dependent manner.

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Degradation of STAT3 in donor T cells prevents acute GVHD in a PD-1–depe...
(A) Splenic T cells from WT or PD-1–/– C57BL/6 mice were treated with or without 40 μM SD-36. T cell expression of STAT3 was measured by immunoblotting after 24 hours. Representative immunoblotting patterns and means ± SEM of expression levels are shown. (B) Irradiated BALB/c recipients were engrafted with TCD-BM (5 × 106) from WT C57BL/6 donors alone or with purified T cells (1 × 106) from spleens of WT or PD-1–/– C57BL/6 donors after culture in medium containing 40 μM SD-36 for 24 hours in vitro. Recipients were treated with SD-36 (50 mg/kg, i.v.) or vehicle on days 0 and 3 after HCT. Plots of percentages of original body weight and clinical GVHD score and percentage survival are shown. n = 3 (TCD-BM); n = 5 (WT T cells+vehicle); n = 6 (WT T cells+SD-36); n = 6 (PD-1–/– T cells+SD36) combined from 2 replicate experiments. (C–H) On day 6 after HCT, lymphocytes from the liver and gut were analyzed with flow cytometry. n = 4–5 combined from 2 replicate experiments. (C) Yield of CD4+ donor T cells are shown. (D and E) Percentage of GM-CSF+IFN-γ+ and TNF-α+IFN-γ+ among CD4+ T cells. (F) Yield of CD8+ donor T cells. (G) Percentages of GM-CSF+IFN-γ+ among CD8+ T cells are shown. n = 5 combined from 2 replicate experiments. (H) MFI of GzmB of CD8+ T cells is shown. n = 4–5 representing means ± SEM. P values were calculated by 2-way ANOVA (A) or unpaired 2-tailed Student t tests (C–H). NS, P ≥ 0.05; *P < 0.05; **P < 0.01; ****P < 0.0001.