Institute of Blood and Marrow Transplantation, Medical College of Soochow University, Soochow University, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore.
Front Immunol. 2018 Nov 26;9:2724. doi: 10.3389/fimmu.2018.02724. eCollection 2018.
Acute graft-vs.-host disease (aGVHD) is one of the major complications and results in high mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-17C is involved in many inflammatory immune disorders. However, the role of IL-17C in aGVHD remains unknown. Here we demonstrated that IL-17C deficiency in the graft significantly promoted alloreactive T cell responses and induced aggravated aGVHD compared with wildtype donors in a fully MHC-mismatched allo-HSCT model. In contrast, IL-17C overexpression ameliorated aGVHD. IL-17C deficiency increased intestinal epithelial permeability and elevated inflammatory cytokine production, leading to an enhanced aGVHD progression. Tregs was reduced in recipients of IL-17C graft, whilst restored after IL-17C overexpression. Decreased Treg differentiation was abrogated after neutralizing IFN-γ, but not IL-6. Moreover, depletion of Tregs diminished the protective effect of IL-17C. Of note, patients with low IL-17C expression displayed higher aGVHD incidence together with poor overall survival, thereby IL-17C could be an independent risk factor for aGVHD development. Our results are the first demonstrating the protective role of IL-17C in aGVHD by promoting intestinal barrier functions and Treg differentiation in a MHC fully mismatched murine aGVHD model. IL-17C may serve as a novel biomarker and potential therapeutic target for aGVHD.
急性移植物抗宿主病（aGVHD）是异基因造血干细胞移植（allo-HSCT）后主要并发症之一，导致高死亡率。IL-17C 参与许多炎症免疫疾病。然而，IL-17C 在 aGVHD 中的作用尚不清楚。在这里，我们证明在完全 MHC 错配的 allo-HSCT 模型中，移植物中 IL-17C 的缺失显著促进了同种反应性 T 细胞反应，并导致与野生型供体相比，加重了 aGVHD。相比之下，IL-17C 的过表达改善了 aGVHD。IL-17C 缺乏增加了肠道上皮通透性并升高了炎症细胞因子的产生，导致 aGVHD 进展增强。IL-17C 移植物受者中的 Treg 减少，而在 IL-17C 过表达后恢复。在中和 IFN-γ 后，Treg 分化减少得到了逆转，但在中和 IL-6 后则没有。此外，Treg 的耗竭减弱了 IL-17C 的保护作用。值得注意的是，IL-17C 表达水平低的患者 aGVHD 发生率更高，总体生存率更差，因此 IL-17C 可能是 aGVHD 发展的一个独立危险因素。我们的结果首次证明，IL-17C 通过促进 MHC 完全错配的小鼠 aGVHD 模型中的肠道屏障功能和 Treg 分化，在 aGVHD 中发挥保护作用。IL-17C 可能作为 aGVHD 的一个新的生物标志物和潜在的治疗靶点。
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