Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Blood. 2011 Jul 14;118(2):446-55. doi: 10.1182/blood-2010-07-294785. Epub 2011 May 19.
IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes.
IL-21 是一种由 Th17 细胞产生的促炎细胞因子。最近的研究表明，阻断 IL-21 信号通路可以减少移植物抗宿主病（GVHD），同时保留移植物抗白血病/淋巴瘤（GVL）反应。然而，IL-21 如何导致 GVHD 和 GVL 的分离机制仍不完全清楚。在 MHC 错配的 BM 移植模型中，我们观察到 IL-21 受体敲除（IL-21R KO）供体 T 细胞在接受移植的受体中介导全身性和胃肠道 GVHD 减少。这种 GVHD 的减少与移植供体调节性 T 细胞的扩增以及 Th 细胞功能的组织特异性调节有关。IL-21R KO 和野生型供体 T 细胞表现出等效的同种异体激活，但 IL-21R KO T 细胞在肠系膜淋巴结内的浸润和炎症细胞因子产生减少。然而，Th 细胞细胞因子的产生在周围得到维持，并且 IL-21R KO T 细胞介导对 A20 和 P815 造血肿瘤的等效免疫。总之，阻断供体 T 细胞中的 IL-21 信号通路会导致免疫的组织特异性调节，从而减少胃肠道 GVHD，但保留外周 T 细胞功能和 GVL 能力。因此，IL-21 是治疗干预和改善临床移植结果的一个令人兴奋的靶点。
