Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections.
Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections.
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多微生物败血症通过减少NK细胞内在受体介导的对病毒配体或感染的效应子应答来影响NK细胞介导的免疫。
DOI：
10.1371/journal.ppat.1007405
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发表时间：
2018-10
期刊：
影响因子：
6.7
通讯作者：
Badovinac VP
中科院分区：
文献类型：
--
作者：
Jensen IJ;Winborn CS;Fosdick MG;Shao P;Tremblay MM;Shan Q;Tripathy SK;Snyder CM;Xue HH;Griffith TS;Houtman JC;Badovinac VP
脓毒症引起的细胞因子风暴导致严重的淋巴细胞减少和剩余/存活细胞的效应能力降低。这导致长期的免疫麻痹状态，导致继发感染后脓毒症幸存者的发病率/死亡率增加。脓毒症对几种淋巴亚群的影响已得到表征，但其对 NK 细胞的影响仍然未被充分认识——尽管它们在控制感染方面发挥着关键作用。在这里，我们观察到盲肠结扎穿刺 (CLP) 诱导的脓毒症后多个组织中 NK 细胞的数量损失。为了阐明败血症引起的存活 NK 细胞损伤，对转录谱进行了评估，并表明与受损的效应器功能一致的变化。二次感染和/或细胞因子刺激（IL-12、IL-18）后 NK 细胞产生效应分子的能力相应缺陷，进一步表明败血症诱导的 NK 细胞内在损伤。为了特异性探测 NK 细胞受体介导的功能，识别鼠巨细胞病毒 (MCMV) m157 蛋白的激活 Ly49H 受体作为模型受体。尽管 Ly49H 受体的相对表达没有改变，但 CLP 宿主中 Ly49H+ NK 细胞的数量减少，导致体内细胞毒性受损，并且 NK 细胞（基于每个细胞）在体外执行 Ly49H 介导的脱颗粒、杀伤和效应分子产生的能力也严重降低。从机制上讲，通过 TIRF 显微镜评估的 Ly49H 接头蛋白 (DAP12) 激活和聚类受到损害。这进一步与受体刺激后 AKT 磷酸化和钙流动能力的减弱有关。重要的是，NK 细胞中 DAP12 的过度表达恢复了 CLP 宿主中 Ly49H/D 受体介导的效应功能。最后，由于 Ly49H+ NK 细胞中脓毒症依赖性的数量和功能损伤，宿主控制 MCMV 感染的能力显着受损。重要的是，CLP 后的 IL-2 复合物 (IL-2c) 治疗改善了 NK 细胞的数量，但没有改善其功能，从而增强了对 MCMV 攻击的免疫力。因此，脓毒症引起的免疫麻痹状态包括数值和 NK 细胞内在功能损伤，这对未来旨在恢复脓毒症幸存者 NK 细胞免疫的研究具有指导意义。脓毒症是宿主对感染的过度反应，最初可能导致脓毒症幸存者显着发病/死亡和长期免疫麻痹状态。脓毒症引起的免疫麻痹会功能性损害许多淋巴细胞群，包括 NK 细胞。然而，NK 细胞损伤的范围和潜在机制以及 NK 细胞介导的病原体控制的后果仍然未被充分认识。 NK 细胞通过激活和抑制受体的平衡有助于宿主对病原体的早期控制，而 NK 细胞发挥受体介导免疫的数量和能力的改变可能会导致宿主对感染的控制受到严重损害。本研究定义了脓毒症引起的 NK 细胞对细胞因子刺激和受体信号传导反应的数值和细胞内在功能损伤，这些损伤导致宿主启动 NK 细胞介导的效应反应并为细菌和/或病毒病原体提供保护的能力受损。受体信号传导受损是由于接头蛋白 DAP12 表达减少所致。重要的是，CLP 宿主的 NK 细胞提供抗病毒 (MCMV) 免疫力的能力减弱，可通过 IL-2 复合物 (IL-2c) 疗法部分恢复，该疗法增加了保护性 Ly49H+ NK 细胞的数量，但没有提高其功能。因此，这些发现定义了脓毒症引起的 NK 细胞区室的变化，并为旨在解决脓毒症幸存者中脓毒症引起的免疫麻痹的潜在治疗干预措施提供了见解。
The sepsis-induced cytokine storm leads to severe lymphopenia and reduced effector capacity of remaining/surviving cells. This results in a prolonged state of immunoparalysis, that contributes to enhanced morbidity/mortality of sepsis survivors upon secondary infection. The impact of sepsis on several lymphoid subsets has been characterized, yet its impact on NK-cells remains underappreciated–despite their critical role in controlling infection(s). Here, we observed numerical loss of NK-cells in multiple tissues after cecal-ligation-and-puncture (CLP)-induced sepsis. To elucidate the sepsis-induced lesions in surviving NK-cells, transcriptional profiles were evaluated and indicated changes consistent with impaired effector functionality. A corresponding deficit in NK-cell capacity to produce effector molecules following secondary infection and/or cytokine stimulation (IL-12,IL-18) further suggested a sepsis-induced NK-cell intrinsic impairment. To specifically probe NK-cell receptor-mediated function, the activating Ly49H receptor, that recognizes the murine cytomegalovirus (MCMV) m157 protein, served as a model receptor. Although relative expression of Ly49H receptor did not change, the number of Ly49H+ NK-cells in CLP hosts was reduced leading to impaired in vivo cytotoxicity and the capacity of NK-cells (on per-cell basis) to perform Ly49H-mediated degranulation, killing, and effector molecule production in vitro was also severely reduced. Mechanistically, Ly49H adaptor protein (DAP12) activation and clustering, assessed by TIRF microscopy, was compromised. This was further associated with diminished AKT phosphorylation and capacity to flux calcium following receptor stimulation. Importantly, DAP12 overexpression in NK-cells restored Ly49H/D receptors-mediated effector functions in CLP hosts. Finally, as a consequence of sepsis-dependent numerical and functional lesions in Ly49H+ NK-cells, host capacity to control MCMV infection was significantly impaired. Importantly, IL-2 complex (IL-2c) therapy after CLP improved numbers but not a function of NK-cells leading to enhanced immunity to MCMV challenge. Thus, the sepsis-induced immunoparalysis state includes numerical and NK-cell-intrinsic functional impairments, an instructive notion for future studies aimed in restoring NK-cell immunity in sepsis survivors. Sepsis is an exaggerated host response to infection that can initially lead to significant morbidity/mortality and a long-lasting state of immunoparalysis in sepsis survivors. Sepsis-induced immunoparalysis functionally impairs numerous lymphocyte populations, including NK-cells. However, the scope and underlying mechanisms of NK-cell impairment and the consequences for NK-cell-mediated pathogen control remain underappreciated. NK-cells contribute to early host control of pathogens through a balance of activating and inhibitory receptors, and alterations in the number and capacity of NK-cells to exert receptor-mediated immunity can lead to dramatic impairment in host control of infection. The present study defines sepsis-induced numerical and cell-intrinsic functional impairments in NK-cell response to cytokine stimulation and receptor signaling that contribute to impaired host capacity to mount NK-cell-mediated effector responses and provide protection to bacterial and/or viral pathogens. Impairments in receptor signaling were due to reduced expression of adaptor protein DAP12. Importantly, the diminished ability of NK-cells from CLP hosts to provide anti-viral (MCMV) immunity is partially restored by IL-2 complex (IL-2c) therapy, which increased the number, but not function, of protective Ly49H+ NK-cells. Thus, these findings define sepsis-induced changes of the NK-cell compartment and provide insight into potential therapeutic interventions aimed at resolving sepsis-induced immunoparalysis in sepsis survivors.
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影响因子：
4.4
作者：
Davis, Aja H.;Guseva, Natalya V.;Heusel, Jonathan W.
通讯作者：
Heusel, Jonathan W.
影响因子：
4.8
作者：
Bilal MY;Zhang EY;Dinkel B;Hardy D;Yankee TM;Houtman JC
通讯作者：
Houtman JC
DOI：
10.4049/jimmunol.1700375
发表时间：
2017-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen CW;Mittal R;Klingensmith NJ;Burd EM;Terhorst C;Martin GS;Coopersmith CM;Ford ML
通讯作者：
Ford ML
DOI：
10.1084/jem.171.1.173
发表时间：
1990-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Biron CA;Young HA;Kasaian MT
通讯作者：
Kasaian MT
影响因子：
4.8
作者：
Chang, Katherine C.;Unsinger, Jacqueline;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.