Downregulation of HLA Class I Renders Inflammatory Neutrophils More Susceptible to NK Cell-Induced Apoptosis

Abstract

Neutrophils are potent effector cells and contain a battery of harmful substances and degrading enzymes. A silent neutrophil death, i.e., apoptosis, is therefore of importance to avoid damage to the surrounding tissue and to enable termination of the acute inflammatory process. There is a pile of evidence supporting the role for pro-inflammatory cytokines in extending the life-span of neutrophils, but relatively few studies have been devoted to mechanisms actively driving apoptosis induction in neutrophils. We have previously demonstrated that natural killer (NK) cells can promote apoptosis in healthy neutrophils. In this study, we set out to investigate how neutrophil sensitivity to NK cell-mediated cytotoxicity is regulated under inflammatory conditions. Using in vitro-activated neutrophils and a human skin chamber model that allowed collection of in vivo-transmigrated neutrophils, we performed a comprehensive characterization of neutrophil expression of ligands to NK cell receptors. These studies revealed a dramatic downregulation of HLA class I molecules in inflammatory neutrophils, which was associated with an enhanced susceptibility to NK cell cytotoxicity. Collectively, our data shed light on the complex regulation of interactions between NK cells and neutrophils during an inflammatory response and provide further support for a role of NK cells in the resolution phase of inflammation.

STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features

“…The overall (more pronounced) reduction of blood-cell counts observed for several myeloid and lymphoid populations in STAT3mutated vs. WT LGLL cases might be explained by the fact that common surface molecules shared by all the reduced hematopoietic cells could trigger cytotoxicity by clonal LGLs. In this sense, markers such as CD45, CD244, and HLA-I are present or expressed with higher intensity on the surface of neutrophils, eosinophils, dendritic cells, nonclassical monocytes, and NK cells [38][39][40][41][42] which could be potentially recognized by clonal LGLs, and trigger LGL-mediated cytotoxic mechanisms involved in the death/elimination of the target cells. Further studies are needed to confirm which of these or other markers shared by the different leukocyte-cell subsets decreased in T/NK-LGLL patients are potentially targeted by cytotoxic clonal T/NK-LGLs, particularly in STAT3-mutated cases, leading to LGLL-associated cytopenias.…”

Docosahexaenoic Acid Modulates NK Cell Effects on Neutrophils and Their Crosstalk

“…NK cells have been shown to induce neutrophil apoptosis through NKp46 and/or Fas-signaling or by diminishing MHC class I expression on neutrophils ( 16 , 17 ). In addition, NK cells are suggested to either inhibit or increase neutrophil apoptosis through a GM-CSF-mediated mechanism ( 7 , 8 , 17 ). In the present study, we examined the kinetics of the effects of NK cells on neutrophil apoptosis, to shed light on these contradicting results.…”

“…and Thorén et al. also investigating apoptosis at early time-points ( 16 , 17 ). By contrast, prolonged co-culture (18 h) of NK cells and neutrophils suppressed neutrophil apoptosis, comparable to that shown by Bhatnagar et al.…”

“…NK cells induce neutrophil apoptosis in fungal infections ( 15 ) through NKp46- and/or Fas-dependent mechanisms ( 16 ) and upregulation of MHC class I expression on neutrophils is associated with higher susceptibility to NK cell-induced apoptosis ( 17 ). On the contrary, two independent studies have shown that NK cells inhibit neutrophil apoptosis in vitro ( 7 , 8 ).…”

miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy

“…In fact, NK cells do not need to be primed with antigens to become fully functional and the mechanisms of non-self recognition do not rely on genomic recombination and subsequent cell clone expansion events. Nowadays it is recognized that these cells mediate immunesurveillance also via regulatory functions by secreting cytokines, primarily interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), and by interacting with other immune or adaptive immune cells (Marcenaro et al, 2006;Vivier et al, 2011;Riise et al, 2015;Pesce et al, 2017b;Bernson et al, 2019). In turn, NK cells can respond to different types of chemokines and cytokines produced by other immune cells (Marcenaro et al, 2005a(Marcenaro et al, ,b, 2006Moretta et al, 2006;Parodi et al, 2015;Pesce et al, 2016).…”