STING-dependent type I IFN production inhibits cell-mediated immunity to Listeria monocytogenes.
STING-dependent type I IFN production inhibits cell-mediated immunity to Listeria monocytogenes.
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DOI：
10.1371/journal.ppat.1003861
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发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
Portnoy DA
中科院分区：
文献类型：
--
作者：
Archer KA;Durack J;Portnoy DA
感染进入宿主细胞胞质溶胶的单核细胞增生李斯特菌菌株导致强烈的细胞毒性T细胞应答，从而导致长寿命的细胞介导的免疫（CMI）。L.单核细胞增多症分泌环二腺苷单磷酸（c-di-AMP），其激活先天免疫传感器STING，导致IFN-β和共调节基因的表达。在这项研究中，我们研究了STING在保护性CMI发展中的作用。单核细胞增多症STING或其下游效应子IRF 3缺陷的小鼠限制了L.单核细胞增多症，并表现出增强的免疫力，这是MyD 88的独立性。相反，通过共同施用c-di-AMP或通过感染L.分泌升高水平的c-di-AMP的单核细胞增多症突变体导致主要依赖于I型干扰素受体的保护性免疫降低。这些数据表明L. STING的单核细胞增多症激活通过诱导I型干扰素下调CMI。目前的疫苗在产生中和抗体方面是成功的，然而，迫切的医学需求是找到产生长寿记忆T细胞的佐剂。用细菌单核细胞增生李斯特菌免疫诱导由细胞毒性淋巴细胞介导的强大的保护性免疫应答，所述细胞毒性淋巴细胞在再感染时有效地杀死感染的细胞。当L.当单核细胞增多症进入细胞时，它分泌小分子环二腺苷一磷酸（c-di-AMP），其激活宿主蛋白STING，导致I型干扰素应答。在这项研究中，我们使用小鼠免疫模型测试了STING激活是否在细胞毒性淋巴细胞和保护性免疫的产生中发挥作用。我们发现，在没有STING信号的情况下，小鼠在再感染时限制细菌生长并保持较高数量的细胞毒性淋巴细胞，而在存在升高水平的c-di-AMP的情况下免疫的小鼠受到的保护较少。这些结果表明，由细菌病原体诱导的炎症可能不利于适应性免疫的发展，这可能为疫苗开发提供新的见解。
Infection with Listeria monocytogenes strains that enter the host cell cytosol leads to a robust cytotoxic T cell response resulting in long-lived cell-mediated immunity (CMI). Upon entry into the cytosol, L. monocytogenes secretes cyclic diadenosine monophosphate (c-di-AMP) which activates the innate immune sensor STING leading to the expression of IFN-β and co-regulated genes. In this study, we examined the role of STING in the development of protective CMI to L. monocytogenes. Mice deficient for STING or its downstream effector IRF3 restricted a secondary lethal challenge with L. monocytogenes and exhibited enhanced immunity that was MyD88-independent. Conversely, enhancing STING activation during immunization by co-administration of c-di-AMP or by infection with a L. monocytogenes mutant that secretes elevated levels of c-di-AMP resulted in decreased protective immunity that was largely dependent on the type I interferon receptor. These data suggest that L. monocytogenes activation of STING downregulates CMI by induction of type I interferon. Current vaccines are successful at generating neutralizing antibodies, however there is a pressing medical need to find adjuvants that yield long-lived memory T cells. Immunization with the bacterium Listeria monocytogenes induces a robust protective immune response mediated by cytotoxic lymphocytes that are efficient at killing infected cells upon reinfection. When L. monocytogenes enters a cell, it secretes the small molecule cyclic diadenosine monophosphate (c-di-AMP), which activates the host protein STING leading to a type I interferon response. In this study, we tested whether STING activation plays a role in the generation of cytotoxic lymphocytes and protective immunity using a mouse immunization model. We found that in the absence of STING signaling mice restricted bacterial growth and maintained higher numbers of cytotoxic lymphocytes upon reinfection, whereas mice immunized in the presence of elevated levels of c-di-AMP were less protected. These results suggest that the inflammation induced by a bacterial pathogen can be detrimental to the development of adaptive immunity, which could provide new insights into vaccine development.
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64.8
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