Université de Paris, Inserm U1016, CNRS UMR 8104, and Cochin Hospital, Paris, France.
Université de Paris, Inserm U1016, CNRS UMR 8104, Paris, France.
Arthritis Rheumatol. 2022 Aug;74(8):1387-1398. doi: 10.1002/art.42111. Epub 2022 Jun 28.
Systemic sclerosis (SSc) is a debilitating autoimmune disease characterized by severe lung outcomes resulting in reduced life expectancy. Fra-2-transgenic mice offer the opportunity to decipher the relationships between the immune system and lung fibrosis. This study was undertaken to investigate whether the Fra-2-transgenic mouse lung phenotype may result from an imbalance between the effector and regulatory arms in the CD4+ T cell compartment.
We first used multicolor flow cytometry to extensively characterize homeostasis and the phenotype of peripheral CD4+ T cells from Fra-2-transgenic mice and control mice. We then tested different treatments for their effectiveness in restoring CD4+ Treg cell homeostasis, including adoptive transfer of Treg cells and treatment with low-dose interleukin-2 (IL-2).
Fra-2-transgenic mice demonstrated a marked decrease in the proportion and absolute number of peripheral Treg cells that preceded accumulation of activated, T helper cell type 2-polarized, CD4+ T cells. This defect in Treg cell homeostasis was derived from a combination of mechanisms including impaired generation of these cells in both the thymus and the periphery. The impaired ability of peripheral conventional CD4+ T cells to produce IL-2 may greatly contribute to Treg cell deficiency in Fra-2-transgenic mice. Notably, adoptive transfer of Treg cells, low-dose IL-2 therapy, or combination therapy changed the phenotype of Fra-2-transgenic mice, resulting in a significant reduction in pulmonary parenchymal fibrosis and vascular remodeling in the lungs.
Immunotherapies for restoring Treg cell homeostasis could be relevant in SSc. An intervention based on low-dose IL-2 injections, as is already proposed in other autoimmune diseases, could be the most suitable treatment modality for restoring Treg cell homeostasis for future research.
系统性硬化症（SSc）是一种使人衰弱的自身免疫性疾病，其肺部严重病变导致预期寿命缩短。Fra-2 转基因小鼠为阐明免疫系统与肺纤维化之间的关系提供了机会。本研究旨在探讨 Fra-2 转基因小鼠的肺部表型是否源于 CD4+T 细胞区室中效应器和调节臂之间的失衡。
我们首先使用多色流式细胞术来广泛描述 Fra-2 转基因小鼠和对照小鼠的外周 CD4+T 细胞的稳态和表型。然后，我们测试了不同的治疗方法对恢复 CD4+Treg 细胞稳态的有效性，包括 Treg 细胞的过继转移和低剂量白细胞介素-2（IL-2）的治疗。
Fra-2 转基因小鼠表现出外周 Treg 细胞比例和绝对数量的显著减少，随后出现活化的、辅助性 T 细胞 2 极化的 CD4+T 细胞的积累。这种 Treg 细胞稳态缺陷源于多种机制，包括在胸腺和外周中这些细胞的生成受损。外周常规 CD4+T 细胞产生 IL-2 的能力受损可能极大地促成了 Fra-2 转基因小鼠中的 Treg 细胞缺陷。值得注意的是，Treg 细胞过继转移、低剂量 IL-2 治疗或联合治疗改变了 Fra-2 转基因小鼠的表型，导致肺部实质纤维化和血管重塑显著减少。
恢复 Treg 细胞稳态的免疫疗法可能与 SSc 相关。基于低剂量 IL-2 注射的干预措施，如已经在其他自身免疫性疾病中提出的那样，可能是恢复 Treg 细胞稳态的最适合治疗方式，为未来的研究提供了思路。
