Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections

Isaac J Jensen, Christina S Winborn, Micaela G Fosdick, Peng Shao, Mikaela M Tremblay, Qiang Shan, Sandeep Kumar Tripathy, Christopher M Snyder, Hai-Hui Xue, Thomas S Griffith, Jon C Houtman and Vladimir P Badovinac

PLOS Pathogens, 2018, vol. 14, issue 10, 1-36

Abstract: 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.Author summary: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:plo:ppat00:1007405

DOI: 10.1371/journal.ppat.1007405

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