Natural Killer Cells Dampen the Pathogenic Features of Recall Responses to Influenza Infection

Abstract

Despite evidence of augmented Natural Killer (NK) cell responses after influenza vaccination, the role of these cells in vaccine-induced immunity remains unclear. Here, we hypothesized that NK cells might increase viral clearance but possibly at the expense of increased severity of pathology. On the contrary, we found that NK cells serve a homeostatic role during influenza virus infection of vaccinated mice, allowing viral clearance with minimal pathology. Using a diphtheria toxin receptor transgenic mouse model, we were able to specifically deplete NKp46+ NK cells through the administration of diphtheria toxin. Using this model, we assessed the effect of NK cell depletion prior to influenza challenge in vaccinated and unvaccinated mice. NK-depleted, vaccinated animals lost significantly more weight after viral challenge than vaccinated NK intact animals, indicating that NK cells ameliorate disease in vaccinated animals. However, there was also a significant reduction in viral load in NK-depleted, unvaccinated animals indicating that NK cells also constrain viral clearance. Depletion of NK cells after vaccination, but 21 days before infection, did not affect viral clearance or weight loss-indicating that it is the presence of NK cells during the infection itself that promotes homeostasis. Further work is needed to identify the mechanism(s) by which NK cells regulate adaptive immunity in influenza-vaccinated animals to allow efficient and effective virus control whilst simultaneously minimizing inflammation and pathology.

Polymer formulated self-amplifying RNA vaccine is partially protective against influenza virus infection in ferrets

“…This is not uncommon in ferret studies—for example there was detectable virus after immunization with an HA stem fragment [ 35 ] (which differed to the mouse model in the same study), a live attenuated virus vaccine [ 36 ] or an adjuvanted protein vaccine [ 37 ]. Direct neutralization may not be the only function of anti-HA antibodies in protection, we have previously observed that NK cells are required for vaccine protection [ 38 ] and a recent study showed an association between NK activating antibodies and lower respiratory tract control of RSV [ 39 ]. These functional, but non-neutralizing antibodies may bind other, more conserved regions of HA, for example the stem.…”

NK cells at the crossroads in COVID-19: a question of timing

“…In a mouse model of high dose influenza infection, it was the depletion of NK cells that ameliorated the virusinduced pathology in the lungs (Abdul-Careem et al, 2012). In contrast, other reports show that NK cells, perhaps via IL-22 production (Kumar et al, 2013), are essential for down-regulating pathogenic inflammatory responses and maintaining equilibrium after influenza vaccination (Mooney et al, 2020) and also in diabetes and coronary arterial disease (Gong et al, 2016).…”

Cellular and Molecular Immunity to Influenza Viruses and Vaccines

“…However, it was noted that the inactivated viral strains in TIV do not decrease the presence of CD112 and CD54 on the surface of the monocyte cells [83]. A study of seasonal flu vaccinated mice showed that NK cells are responsible for decreasing illness after infection by a pandemic flu strain, such as A/California/4/2009 [84].…”