Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
J Immunol. 2019 Jun 1;202(11):3161-3172. doi: 10.4049/jimmunol.1801159. Epub 2019 Apr 24.
A defect in TCR-proximal signaling is a major characteristic of CD4 T cells in systemic lupus erythematosus; however, it is not fully known how defects in TCR signaling lead to lupus-like systemic autoimmunity characterized by germinal center development and autoantibody production against nuclear Ags. In this study, we show that SKG mice, which develop autoimmune arthritis in a BALB/c background due to defective TCR signaling by a mutation, develop lupus-like systemic autoimmune disease in the C57BL/6 (B6) background (B6SKG mice). B6SKG mice showed multiorgan inflammation with immune complex deposition and anti-dsDNA Ab production. Follicular helper T cells (Tfh), which help germinal center formation, were spontaneously expanded in B6SKG mice. Th cells secreting IFN-γ or IL-17 and regulatory T cells were also increased in B6SKG mice compared with wild-type B6 mice, with the regulatory T cell subpopulation losing the expression of CD25. Among the factors related to Tfh differentiation, the number of dendritic cells and the expression levels of the costimulatory molecules CD80, CD86, and ICOSL in dendritic cells but not in B cells were specifically increased in wild-type B6 mice compared with BALB/c mice. The inhibition of these costimulatory molecules suppressed Tfh development and lupus-like autoimmunity. Thus, a defect in TCR-proximal signaling leads to lupus-like systemic autoimmunity under the specific genetic background that facilitates Tfh development.
T 细胞受体（TCR）近端信号缺陷是系统性红斑狼疮（SLE）CD4 T 细胞的主要特征；然而，TCR 信号缺陷如何导致以生发中心发育和针对核抗原产生自身抗体为特征的狼疮样系统性自身免疫尚不完全清楚。在这项研究中，我们发现由于 TCR 信号缺陷，在 BALB/c 背景下会发展出自发性关节炎的 SKG 小鼠，在 C57BL/6（B6）背景下（B6SKG 小鼠）会发展出狼疮样系统性自身免疫性疾病。B6SKG 小鼠表现出多器官炎症，伴有免疫复合物沉积和抗双链 DNA（dsDNA）Ab 的产生。滤泡辅助性 T 细胞（Tfh）可帮助生发中心形成，在 B6SKG 小鼠中自发性扩增。与野生型 B6 小鼠相比，B6SKG 小鼠中分泌 IFN-γ 或 IL-17 的 Th 细胞和调节性 T 细胞也增加，调节性 T 细胞亚群失去了 CD25 的表达。在与 Tfh 分化相关的因子中，与 BALB/c 小鼠相比，树突状细胞的数量以及树突状细胞而非 B 细胞中共刺激分子 CD80、CD86 和 ICOSL 的表达水平在野生型 B6 小鼠中特异性增加。这些共刺激分子的抑制抑制了 Tfh 的发育和狼疮样自身免疫。因此，TCR 近端信号缺陷在促进 Tfh 发育的特定遗传背景下导致狼疮样系统性自身免疫。
