STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection
STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection
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DOI：
10.1172/jci80273
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发表时间：
2015-06-01
影响因子：
15.9
通讯作者：
Feske, Stefan
中科院分区：
文献类型：
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作者：
Desvignes, Ludovic;Weidinger, Carl;Feske, Stefan
慢性感染诱导控制病原体复制的复杂免疫应答，但也由于持续的炎症引起病理学。Ca 2+内流介导T细胞功能和对感染的免疫力，并且在编码Ca 2+通道ORAI 1或其激活剂基质相互作用分子1（STIM 1）的基因中具有遗传突变的患者是免疫缺陷的，并且易于受到各种病原体（包括结核分枝杆菌（Mtb））的慢性感染。在这里，我们证明了STIM 1是慢性结核分枝杆菌感染期间T细胞介导的免疫调节所必需的。与WT动物相比，T细胞特异性Stim 1缺失的小鼠在感染的慢性期过早死亡，细菌负荷增加，肺部炎症严重，骨髓和淋巴细胞浸润增加。尽管STIM 1缺陷型T细胞在结核分枝杆菌感染的早期阶段表现出IFN-γ产生显著减少，但细菌生长并没有立即加剧。然而，在慢性期，STIM 1缺陷型T细胞显示出响应于IL-12和IL-18水平升高而增强的IFN-γ产生。在Mtb感染的小鼠中，T细胞中STIM 1的缺乏与反复TCR接合和肺淋巴细胞增多和炎症过度后活化诱导的细胞死亡受损相关。慢性Mtb感染的STIM 1缺陷小鼠由于在iTreg分化中对STIM 1的T细胞内在需求以及抑制iTreg分化和维持的IFN-γ和IL-12的过量产生而具有降低的诱导型调节性T细胞（iTcells）水平。因此，STIM 1控制T细胞介导的免疫调节的多个方面，以限制慢性感染期间的有害炎症。
Chronic infections induce a complex immune response that controls pathogen replication, but also causes pathology due to sustained inflammation. Ca2+ influx mediates T cell function and immunity to infection, and patients with inherited mutations in the gene encoding the Ca2+ channel ORAI1 or its activator stromal interaction molecule 1 (STIM1) are immunodeficient and prone to chronic infection by various pathogens, including Mycobacterium tuberculosis (Mtb). Here, we demonstrate that STIM1 is required for T cell-mediated immune regulation during chronic Mtb infection. Compared with WT animals, mice with T cell-specific Stim1 deletion died prematurely during the chronic phase of infection and had increased bacterial burdens and severe pulmonary inflammation, with increased myeloid and lymphoid cell infiltration. Although STIM1-deficient T cells exhibited markedly reduced IFN-gamma production during the early phase of Mtb infection, bacterial growth was not immediately exacerbated. During the chronic phase, however, STIM1-deficient T cells displayed enhanced IFN-gamma production in response to elevated levels of IL-12 and IL-18. The lack of STIM1 in T cells was associated with impaired activation-induced cell death upon repeated TCR engagement and pulmonary lymphocytosis and hyperinflammation in Mtb-infected mice. Chronically Mtb-infected, STIM1-deficient mice had reduced levels of inducible regulatory T cells (iTregs) due to a T cell-intrinsic requirement for STIM1 in iTreg differentiation and excessive production of IFN-y and IL-12, which suppress iTreg differentiation and maintenance. Thus, STIM1 controls multiple aspects of T cell-mediated immune regulation to limit injurious inflammation during chronic infection.