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Abstract：
UNASSIGNED: Interstitial lung disease (ILD), characterized by pulmonary fibrosis (PF), represents the end-stage of various ILDs. The immune system plays an important role in the pathogenesis of PF. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is an immune checkpoint with immune suppressive functions. However, its specific role in the development of PF and the underlying mechanisms remain to be elucidated.
UNASSIGNED: We assessed the expression of VISTA in CD4 T cells from patients with connective tissue disease-related interstitial lung disease (CTD-ILD). Spleen cells from wild-type (WT) or Vsir -/- mice were isolated and induced for cell differentiation in vitro. Additionally, primary lung fibroblasts were isolated and treated with interleukin-17A (IL-17A). Mice were challenged with bleomycin (BLM) following VISTA blockade or Vsir knockout. Moreover, WT or Vsir -/- CD4 T cells were transferred into Rag1 -/- mice, which were then challenged with BLM.
UNASSIGNED: VISTA expression was decreased in CD4 T cells from patients with CTD-ILD. Vsir deficiency augmented T-helper 17 (Th17) cell differentiation in vitro. Furthermore, IL-17A enhanced the production of inflammatory cytokines, as well as the differentiation and migration of lung fibroblasts. Both VISTA blockade and knockout of Vsir increased the percentage of IL-17A-producing Th17 cells and promoted BLM-induced PF. In addition, mice receiving Vsir -/- CD4 T cells exhibited a higher percentage of Th17 cells and more severe PF compared to those receiving WT CD4 T cells.
UNASSIGNED: These findings demonstrate the significant role of VISTA in modulating the development of PF by controlling Th17 cell differentiation. These insights suggest that targeting VISTA could be a promising therapeutic strategy for PF.
UNASSIGNED: We assessed the expression of VISTA in CD4 T cells from patients with connective tissue disease-related interstitial lung disease (CTD-ILD). Spleen cells from wild-type (WT) or Vsir -/- mice were isolated and induced for cell differentiation in vitro. Additionally, primary lung fibroblasts were isolated and treated with interleukin-17A (IL-17A). Mice were challenged with bleomycin (BLM) following VISTA blockade or Vsir knockout. Moreover, WT or Vsir -/- CD4 T cells were transferred into Rag1 -/- mice, which were then challenged with BLM.
UNASSIGNED: VISTA expression was decreased in CD4 T cells from patients with CTD-ILD. Vsir deficiency augmented T-helper 17 (Th17) cell differentiation in vitro. Furthermore, IL-17A enhanced the production of inflammatory cytokines, as well as the differentiation and migration of lung fibroblasts. Both VISTA blockade and knockout of Vsir increased the percentage of IL-17A-producing Th17 cells and promoted BLM-induced PF. In addition, mice receiving Vsir -/- CD4 T cells exhibited a higher percentage of Th17 cells and more severe PF compared to those receiving WT CD4 T cells.
UNASSIGNED: These findings demonstrate the significant role of VISTA in modulating the development of PF by controlling Th17 cell differentiation. These insights suggest that targeting VISTA could be a promising therapeutic strategy for PF.
摘要：
■间质性肺病（ILD），以肺纤维化（PF）为特征，表示各种ILD的结束阶段。免疫系统在PF的发病机制中起着重要作用。T细胞激活的V域免疫球蛋白抑制剂（VISTA）是具有免疫抑制功能的免疫检查点。然而,其在PF发展中的具体作用和潜在机制仍有待阐明。
■我们评估了结缔组织疾病相关性间质性肺病（CTD-ILD）患者CD4T细胞中VISTA的表达。分离来自野生型(WT)或Vsir-/-小鼠的脾细胞并在体外诱导细胞分化。此外,分离原代肺成纤维细胞并用白细胞介素-17A(IL-17A)处理。在VISTA阻断或Vsir敲除后,用博来霉素(BLM)攻击小鼠。此外，将WT或Vsir-/-CD4T细胞转移到Rag1-/-小鼠中，然后受到BLM的挑战。
■VISTA在CTD-ILD患者的CD4T细胞中的表达降低。Vsir缺乏症在体外增强了T辅助细胞17（Th17）的分化。此外，IL-17A增强了炎性细胞因子的产生，以及肺成纤维细胞的分化和迁移。VISTA阻断和敲除Vsir都增加了产生IL-17A的Th17细胞的百分比，并促进了BLM诱导的PF。此外,与接受WTCD4T细胞相比，接受Vsir-/-CD4T细胞的小鼠表现出更高的Th17细胞百分比和更严重的PF。
■这些发现证明了VISTA通过控制Th17细胞分化在调节PF发育中的重要作用。这些见解表明，靶向VISTA可能是PF的一种有前途的治疗策略。
■我们评估了结缔组织疾病相关性间质性肺病（CTD-ILD）患者CD4T细胞中VISTA的表达。分离来自野生型(WT)或Vsir-/-小鼠的脾细胞并在体外诱导细胞分化。此外,分离原代肺成纤维细胞并用白细胞介素-17A(IL-17A)处理。在VISTA阻断或Vsir敲除后,用博来霉素(BLM)攻击小鼠。此外，将WT或Vsir-/-CD4T细胞转移到Rag1-/-小鼠中，然后受到BLM的挑战。
■VISTA在CTD-ILD患者的CD4T细胞中的表达降低。Vsir缺乏症在体外增强了T辅助细胞17（Th17）的分化。此外，IL-17A增强了炎性细胞因子的产生，以及肺成纤维细胞的分化和迁移。VISTA阻断和敲除Vsir都增加了产生IL-17A的Th17细胞的百分比，并促进了BLM诱导的PF。此外,与接受WTCD4T细胞相比，接受Vsir-/-CD4T细胞的小鼠表现出更高的Th17细胞百分比和更严重的PF。
■这些发现证明了VISTA通过控制Th17细胞分化在调节PF发育中的重要作用。这些见解表明，靶向VISTA可能是PF的一种有前途的治疗策略。
