Chiba University Graduate School of Medicine, Chiba, Japan.
Arthritis Rheumatol. 2014 Aug;66(8):2079-90. doi: 10.1002/art.38658.
FoxP3 induces Treg cells and prevents autoimmune diseases. However, the precise mechanisms of FoxP3 in the prevention of autoimmune diseases remain unknown. We undertook this study to determine the regulatory roles of FoxP3 in autoimmune inflammation by using FoxP3-mutant sf mice.
We characterized interleukin-21 (IL-21)- producing cells in sf mice. We examined the underlying mechanisms of enhanced IL-21 production in sf mouse CD4+ T cells. We examined the roles of IL-21 and CD8+ T cells in autoimmune inflammation in sf mice using IL-21 receptor (IL-21R)-deficient sf mice.
IL-21-producing c-Maf+CD4+ T cells, which were distinct from Th17 cells, were increased in sf mice. Increased c-Maf expression was involved in enhanced IL-21 production in sf mouse CD4+ T cells. Experiments using bone marrow chimeric mice showed that lack of cell-extrinsic suppression by FoxP3+ Treg cells, but not cell-intrinsic defects in FoxP3 in sf mouse CD4+ T cells, was mainly involved in the development of IL-21-producing c-Maf+CD4+ T cells in sf mice. IL-21R deficiency prolonged survival and reduced multiorgan autoimmune inflammation in sf mice. Moreover, IL-21R deficiency decreased short-lived effector CD8+ T cells in the lung in sf mice. Furthermore, depletion of CD8+ T cells inhibited lung inflammation in sf mice, suggesting that CD8+ T cells are critical for inducing lung inflammation in sf mice.
Unique IL-21-producing c-Maf+ CD4+ T cells develop in the absence of FoxP3+ Treg cells, induce short-lived effector CD8+ T cells, and enhance multiorgan autoimmune inflammation in sf mice.
FoxP3 诱导 Treg 细胞并预防自身免疫性疾病。然而，FoxP3 预防自身免疫性疾病的确切机制尚不清楚。我们通过使用 FoxP3 突变 sf 小鼠进行这项研究，以确定 FoxP3 在自身免疫性炎症中的调节作用。
我们对 sf 小鼠中产生白细胞介素 21（IL-21）的细胞进行了特征描述。我们研究了 sf 小鼠 CD4+T 细胞中增强的 IL-21 产生的潜在机制。我们使用 IL-21 受体（IL-21R）缺陷型 sf 小鼠研究了 IL-21 和 CD8+T 细胞在 sf 小鼠自身免疫性炎症中的作用。
在 sf 小鼠中，增加了产生 IL-21 的 c-Maf+CD4+T 细胞，这些细胞与 Th17 细胞不同。在 sf 小鼠 CD4+T 细胞中，c-Maf 表达增加参与了增强的 IL-21 产生。骨髓嵌合小鼠实验表明，FoxP3+Treg 细胞缺乏细胞外抑制作用，而不是 sf 小鼠 CD4+T 细胞中 FoxP3 的细胞内缺陷，主要涉及 sf 小鼠中产生 IL-21 的 c-Maf+CD4+T 细胞的发育。IL-21R 缺陷延长了 sf 小鼠的存活并减轻了多器官自身免疫性炎症。此外，IL-21R 缺陷减少了 sf 小鼠肺部的短命效应 CD8+T 细胞。此外，耗尽 CD8+T 细胞抑制了 sf 小鼠肺部炎症，表明 CD8+T 细胞对于诱导 sf 小鼠肺部炎症至关重要。
在缺乏 FoxP3+Treg 细胞的情况下，独特的产生 IL-21 的 c-Maf+CD4+T 细胞发育，诱导短命效应 CD8+T 细胞，并增强 sf 小鼠的多器官自身免疫性炎症。
