Effect of Impaired T Cell Receptor Signaling on the Gut Microbiota in a Mouse Model of Systemic Autoimmunity
Effect of Impaired T Cell Receptor Signaling on the Gut Microbiota in a Mouse Model of Systemic Autoimmunity
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T 细胞受体信号传导受损对系统性自身免疫小鼠模型肠道微生物群的影响
DOI：
10.1002/art.42016
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Hashimoto Motomu
中科院分区：
文献类型：
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作者：
Shirakashi Mirei;Maruya Mikako;Hirota Keiji;Tsuruyama Tatsuaki;Matsuo Takashi;Watanabe Ryu;Murata Koichi;Tanaka Masao;Ito Hiromu;Yoshifuji Hajime;Ohmura Koichiro;Elewaut Dirk;Sakaguchi Shimon;Fagarasan Sidonia;Mimori Tsuneyo;Hashimoto Motomu
外周血T细胞受体（TCR）信号传导异常和肠道生态失调被认为参与了系统性红斑狼疮（SLE）的发展。然而，尚不清楚这些机制是否相互关联。本研究旨在探讨缺陷TCR信号传导对微生物群驱动的免疫应答的影响以及随之引发的全身性自身免疫应答。MethodsThe responses of B6 SKG mice harboring a mutation in ZAP-70 leading to spontaneous development of SLE were evaluated under specific pathogen-free（SPF）and germ-free（GF）conditions.使用16 S核糖体RNA测序分析肠道微生物组。分析了肠道中分泌型伊加的产生以及脾脏和派尔集合淋巴结中滤泡辅助T（Tfh）细胞的发育。白细胞介素-17（IL-17）缺陷小鼠和分节丝状菌（SFB）特异性TCR-转基因小鼠被用来检查IL-17和胸腺selection.ResultsSLE的发展中的作用B6 SKG小鼠在GF条件下比SPF条件下显着更衰减。B6 SKG小鼠的肠道微生物群发生了改变，这与SFB的扩张以及随后通过驱动Th 17细胞分化而导致的SLE发展有关，而Th 17细胞分化又因IL-17缺乏而减弱。值得注意的是，虽然全身Tfh发展和自身抗体IgG反应增强，但局部肠道Tfh和伊加反应受损。此外，在SFB特异性TCR转基因小鼠的实验表明，这种差异性反应是由改变胸腺选择的自我和微生物群反应性TCR，因为有缺陷的TCR signaling.ConclusionOur研究结果表明，有缺陷的TCR信号改变肠道微生物群，并通过驱动Th 17细胞分化促进全身性自身免疫。
ObjectiveT cell receptor (TCR) signaling abnormalities and gut dysbiosis are thought to be involved in the development of systemic lupus erythematosus (SLE). However, it is not known whether these mechanisms are interrelated. This study was undertaken to explore the impact of defective TCR signaling on microbiota‐driven immune responses and the consequent triggering of systemic autoimmunity.MethodsThe responses of B6SKG mice harboring a mutation in ZAP‐70 leading to spontaneous development of SLE were evaluated under specific pathogen–free (SPF) and germ‐free (GF) conditions. The gut microbiome was analyzed using 16S ribosomal RNA sequencing. Secretory IgA production in the gut and follicular helper T (Tfh) cell development in the spleen and Peyer's patches were analyzed. Interleukin‐17 (IL‐17)–deficient mice and segmented filamentous bacteria (SFB)–specific TCR‐transgenic mice were used to examine the role of IL‐17 and thymic selection.ResultsSLE development in B6SKG mice was significantly more attenuated under GF conditions than under SPF conditions. The gut microbiota in B6SKG mice was altered, which was associated with the expansion of SFB and consequent development of SLE by driving Th17 cell differentiation, which was in turn blunted by IL‐17 deficiency. Notably, although systemic Tfh development and autoantibody IgG response were enhanced, local gut Tfh and IgA responses were impaired. Moreover, experiments in SFB‐specific TCR‐transgenic mice revealed that this differential response was caused by altered thymic selection of self‐ and microbiota‐reactive TCR because of defective TCR signaling.ConclusionOur findings indicate that defective TCR signaling alters the gut microbiota and promotes systemic autoimmunity by driving Th17 cell differentiation.