Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection

Abstract

Natural killer (NK) cells are indispensable components of both the innate and adaptive immune response. However, their precise roles in the cross-talk between innate and adaptive immunity during influenza virus infection remain controversial. By comparing NK cell dynamics and activity under a sub-lethal dose and high dose of influenza virus infection, we showed that influenza virus PR8 directly infected NK cells during natural infection, which was consistent with our previous findings obtained from an in vitro investigation of human NK cells. The impairments in cytotoxicity and IFN-γ production by spleen NK cells following high-dose infection were accompanied by decreased virus-specific killing mediated by cytotoxic T lymphocytes (CTLs). Importantly, the weakened CTL activity could be reversed by adoptive transfer of spleen NK cells harvested from low-dose-infected mice but not healthy donors. Taken together, our data provide direct evidence supporting the contribution of NK cells to antiviral T-cell responses. This study also indicates that a novel NK-targeted immune evasion strategy is used by influenza virus to shrink both innate and adaptive immune responses.

Respiratory Influenza A Virus Infection Triggers Local and Systemic Natural Killer Cell Activation via Toll-Like Receptor 7

“…In line with this, our results suggest NK cells not to be crucial for anti-IAV defense in a sublethal challenge, as the defects in NK cell activation observed in TLR7-deficient mice did not show effects on the viral load. However, next to ensuring viral clearance, NK cells have been described to serve important functions in shaping adaptive antiviral responses in general ( 23 , 49 , 50 ) and also specifically in IAV infections ( 51 , 52 ). Importantly, TLR7 has also been shown to be significantly involved in the development of fully functional adaptive immune reactions, also in the context of vaccination and persistent viral infection ( 5 , 6 , 9 , 53 – 55 ).…”

Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection

“…Ifn-γ is secreted by T helper cells, cytotoxic T cells, NK cells, and macrophages (37). Ifn-γ promotes adaptive immunity by recruiting CD8 + lymphocytes (39), inducing CD4 + Th1 differentiation (40), activating NK cells (41), and orchestrating T cell responses during IAV infection (42). Infected Mmp-9 -/mice had higher lung Ifn-γ levels that peaked on day 7 p.i., coinciding with elevated Th1 CD4 + , cytotoxic CD8 + T cells, and Th1-like cytotoxic NK cell counts in their lungs.…”

In Silico Vaccine Strain Prediction for Human Influenza Viruses

“…Antibodies can also contribute to the lysis of infected cells via complement activation, antibody dependent cell cytotoxicity or activation of natural killer cells [12][13][14][15][16][17]. The activation of these specific effector mechanisms can lead to improved viral clearance but also to immune pathology, such as more severe forms of disease as a result of immune complexes [18].…”