Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8⁺ and CD4⁺ donor T cells from Itk^-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk^-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

异基因造血干细胞移植是许多恶性疾病的潜在治愈方法。供体 T 细胞预防疾病复发通过移植物抗白血病（GVL）效应。供体 T 细胞也会导致移植物抗宿主病 (GVHD)，这是一种使人衰弱且可能致命的并发症。需要能够保留 GVL 效应而不引起 GVHD 的新治疗策略。使用鼠模型，我们显示靶向供体 T 细胞中的 IL-2 诱导型 T 细胞激酶 (ITK) 可降低 GVHD，同时保留 GVL 效应。CD8 ⁺和 CD4 ⁺供体 T 细胞均来自伊特克^-/-小鼠产生较少的炎性细胞因子，并显示减少向 GVHD 靶器官（如肝脏和小肠）的迁移，同时保持 GVL 对原发性 B 细胞急性淋巴细胞白血病 (B-ALL) 的功效。伊特克^-/-T 细胞表现出 IRF4 表达降低和 JAK/STAT 信号传导活性降低，但上调 Eomesodermin (Eomes) 的表达并保持细胞毒性，这是 GVL 效应所必需的。转录组分析表明 ITK 信号在同种异体激活过程中控制趋化因子受体的表达，进而影响供体 T 细胞迁移到 GVHD 靶器官的能力。我们的数据表明，抑制 ITK 可能是一种减少 GVHD 的治疗策略，同时保留 allo-HSCT 治疗后的有益 GVL 效应。