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

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.

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

“…NK cell dysfunction has become a focus of research interest in recent reports and may be associated with chronic antigenic stimulation and exhaustion (18,221,241,243). This may be due to defective receptor-mediated effector responses (242), and the observations presented here would support that hypothesis.…”

H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation

“…In the context of systemic inflammation, our findings that NK cells acquire memory-like properties, leading to enhanced activation upon re-stimulation, are surprising because the consensus in literature is that NK cell functions are impaired during, and briefly following, acute episodes of sepsis (Guo et al, 2018). Indeed, when stimulated with cytokines, NK cells from acute phase sepsis patients or cecal ligation and puncture (CLP) mice were reported to have suppressed IFNg production and cytotoxicity (Chiche et al, 2012;Jensen et al, 2018;Souza-Fonseca-Guimaraes et al, 2012b, 2012cvon Muller et al, 2007). However, few studies have investigated the post-acute longterm effects of systemic inflammation on NK cells and their cellintrinsic activities independent of the immune environment.…”

NK cells acquire epigenetic memory of LPS-induced systemic inflammation

“…Indeed, when stimulated with cytokines, NK cells from acute phase sepsis patients or cecal-ligation and puncture (CLP) mice were reported to have suppressed IFNg production (16)(17)(18). NK cell cytotoxicity was also shown to be impaired (19,33). However, very few studies have investigated the post-acute long-term effects of systemic inflammation on NK cells and their cell intrinsic activities independent of the immune environment.…”