STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice
STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice
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DOI：
10.1016/j.celrep.2020.107771
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发表时间：
2020-06-16
期刊：
影响因子：
8.8
通讯作者：
Miner, Jonathan J.
中科院分区：
文献类型：
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作者：
Bennion, Brock G.;Croft, Carys A.;Miner, Jonathan J.
STING功能获得导致小鼠自身免疫和免疫缺陷，以及人类与STING相关的婴儿期起病血管病变（SAVI）。在这里，我们报告了小鼠的STING功能获得可以阻止淋巴结和Peyer's补丁的发展。我们发现继发性淋巴器官的缺失与先天淋巴样细胞（ILCs）数量的减少有关，包括淋巴组织诱导剂（LTi）细胞。尽管野生型(WT) α 4 β 7（+）祖细胞能有效地分化为LTi细胞，但STING功能获得性祖细胞却不能。此外，STING的功能获得会损害所有类型ilc的发育。STING功能获得性突变患者的ilc较少，尽管他们仍然有淋巴结。在小鼠中，在ROR γ t阳性谱系中表达STING突变体可以阻止淋巴结的发育并减少LTi细胞的数量。STING功能获得的ROR γ T谱系特异性表达也会导致肺部疾病。由于ROR γ T在胎儿发育期间仅在LTi细胞中表达，我们的研究结果表明，STING功能获得通过减少小鼠LTi细胞数量来阻止淋巴结器官发生。
STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) alpha 4 beta 7(+) progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in ROR gamma T-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. ROR gamma T lineage-specific expression of STING gain-of-function also causes lung disease. Since ROR gamma T is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.