Strain-Specific Manifestation of Lupus-like Systemic Autoimmunity Caused by Zap70 Mutation
Strain-Specific Manifestation of Lupus-like Systemic Autoimmunity Caused by Zap70 Mutation
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DOI：
10.4049/jimmunol.1801159
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发表时间：
2019-06-01
影响因子：
4.4
通讯作者：
Mimori, Tsuneyo
中科院分区：
文献类型：
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作者：
Matsuo, Takashi;Hashimoto, Motomu;Mimori, Tsuneyo
TCR-近端信号缺陷是系统性红斑狼疮中CD4T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抗核AGS自身抗体产生为特征的狼疮样自身免疫尚不完全清楚。在这项研究中，我们发现，在BALB/c背景下，由于ZAP70突变导致TCR信号缺陷而导致自身免疫性关节炎的SKG小鼠在C57BL/6(B6)背景(B6SKG小鼠)中发展为狼疮样自身免疫性疾病。B6SKG小鼠表现为多器官炎症，免疫复合物沉积，抗dsDNA抗体产生。在B6SKG小鼠体内，帮助生发中心形成的滤泡辅助性T细胞(TFH)自发扩增。与野生型B6小鼠相比，B6SKG小鼠分泌干扰素-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CD25的表达。在与Tfh分化相关的因素中，野生型B6小鼠与BALB/c小鼠相比，树突状细胞的数量和共刺激分子CD80、CD86和ICOSL在树突状细胞中的表达水平显著增加，而在B细胞中的表达水平不明显。这些共刺激分子的抑制抑制了TfH的发展和狼疮样自身免疫。因此，在促进Tfh发生的特定遗传背景下，TCR近端信号的缺陷会导致狼疮样系统自身免疫。
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 Zap70 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-gamma 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.