Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Front Immunol. 2022 Aug 2;13:891925. doi: 10.3389/fimmu.2022.891925. eCollection 2022.
CD4Foxp3 regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs promptly respond to low concentrations of IL-2 through the constitutive expression of high-affinity IL-2 receptors. It has been reported that low-dose IL-2 therapy increased circulating Tregs and improved clinical symptoms of chronic GVHD. Clinical studies of IL-2 therapy so far have mainly targeted patients in the chronic phase of transplantation when acute immune responses has subsided. However, the biological and clinical effects of exogenous IL-2 in an acute immune environment have not been well investigated. In the current study, we investigated the impact of exogenous IL-2 therapy on the post-transplant homeostasis of T cell subsets which influence the balance between GVHD and GVL in the acute phase, by setting the various immune environments early after HSCT in murine model. We initially found that 5,000 IU of IL-2 was enough to induce the active proliferation of Treg without influencing other conventional T cells (Tcons) when administered to normal mice. However, activated Tcons showed the response to the same dose of IL-2 in recipients after allogeneic HSCT. In a mild inflammatory environment within a threshold, exogenous IL-2 could effectively modulate Treg homeostasis with just limited influence to activated T cells, which resulted in an efficient GVHD suppression. In contrast, in a severely inflammatory environment, exogenous IL-2 enhanced activated T cells rather than Tregs, which resulted in the exacerbation of GVHD. Of interest, in an immune-tolerant state after transplant, exogenous IL-2 triggered effector T-cells to exert an anti-tumor effect with maintaining GVHD suppression. These data suggested that the responses of Tregs and effector T cells to exogenous IL-2 differ depending on the immune environment in the host, and the mutual balance of the response to IL-2 between T-cell subsets modulates GVHD and GVL after HSCT. Our findings may provide useful information in the optimization of IL-2 therapy, which may be personalized for each patient having different immune status.
CD4+Foxp3+ 调节性 T 细胞（Tregs）在异基因造血干细胞移植（HSCT）后维持免疫耐受中发挥核心作用。Tregs 通过组成性表达高亲和力的 IL-2 受体，对低浓度的 IL-2 迅速作出反应。据报道，低剂量 IL-2 治疗可增加循环 Tregs，并改善慢性移植物抗宿主病（GVHD）的临床症状。迄今为止，IL-2 治疗的临床研究主要针对移植后急性免疫反应消退时处于慢性期的患者。然而，外源性 IL-2 在急性免疫环境中的生物学和临床作用尚未得到很好的研究。在本研究中，我们通过在小鼠模型中在 HSCT 后早期设置各种免疫环境，研究了外源性 IL-2 治疗对影响急性相 GVHD 与 GVL 平衡的 T 细胞亚群移植后稳态的影响。我们最初发现，在正常小鼠中，给予 5000IU 的 IL-2 足以诱导 Treg 的主动增殖，而不影响其他常规 T 细胞（Tcons）。然而，在异基因 HSCT 后的受者中，活化的 Tcons 对相同剂量的 IL-2 作出反应。在阈值内的轻度炎症环境中，外源性 IL-2 可以有效地调节 Treg 稳态，而对活化的 T 细胞只有有限的影响，从而有效地抑制 GVHD。相比之下，在严重炎症环境中，外源性 IL-2 增强了活化的 T 细胞而不是 Tregs，导致 GVHD 加重。有趣的是，在移植后的免疫耐受状态下，外源性 IL-2 触发效应 T 细胞发挥抗肿瘤作用，同时保持 GVHD 抑制。这些数据表明，Tregs 和效应 T 细胞对外源性 IL-2 的反应因宿主的免疫环境而异，T 细胞亚群对 IL-2 的反应相互平衡调节 HSCT 后的 GVHD 和 GVL。我们的研究结果可能为 IL-2 治疗的优化提供有用的信息，这可能针对每个具有不同免疫状态的患者进行个性化治疗。
