Bacterial Manipulation of NK Cell Regulatory Activity Increases Susceptibility to Listeria monocytogenes Infection

Abstract

Natural killer (NK) cells produce interferon (IFN)-γ and thus have been suggested to promote type I immunity during bacterial infections. Yet, Listeria monocytogenes (Lm) and some other pathogens encode proteins that cause increased NK cell activation. Here, we show that stimulation of NK cell activation increases susceptibility during Lm infection despite and independent from robust NK cell production of IFNγ. The increased susceptibility correlated with IL-10 production by responding NK cells. NK cells produced IL-10 as their IFNγ production waned and the Lm virulence protein p60 promoted induction of IL-10 production by mouse and human NK cells. NK cells consequently exerted regulatory effects to suppress accumulation and activation of inflammatory myeloid cells. Our results reveal new dimensions of the role played by NK cells during Lm infection and demonstrate the ability of this bacterial pathogen to exploit the induction of regulatory NK cell activity to increase host susceptibility.

Commensal microbes provide first line defense against Listeria monocytogenes infection

“…2 B). This result is consistent with previous demonstrations of the importance of early innate sources of IFN-γ for effective immune responses in systemic L. monocytogenes infection (Dunn andNorth, 1991 Ladel et al, 1996;Thäle and Kiderlen, 2005), although NKs have also been shown to reduce resistance during early phases of Listeria infection after intravenous inoculation of WT mice (Teixeira and Kaufmann, 1994;Viegas et al, 2013;Clark et al, 2016).…”

A Listeria-Derived Polypeptide Promotes In Vivo Activation of NK Cells for Antitumor Therapy

“…Expression of p60 by Lm was also shown to boost activation and IFNγ secretion by NK cells co-cultured with infected BMDC (21,23). The ability to promote NK cell activation appears to benefit Lm because IFNγ secreting NK cells responding to p60/L1S rapidly switch to secretion of IL-10 (21).…”

“…Expression of p60 by Lm was also shown to boost activation and IFNγ secretion by NK cells co-cultured with infected BMDC (21,23). The ability to promote NK cell activation appears to benefit Lm because IFNγ secreting NK cells responding to p60/L1S rapidly switch to secretion of IL-10 (21). IL-10 has been argued both to promote anti-tumor resistance in the B16.F10 model (32), and to promote growth of B16.F10 melanoma cells (34).…”

“…In addition to mouse DC and NK cells, recombinant L1S protein stimulates human DC and NK cells in cell culture models (21). Activation in these cell cultures requires the presence of contaminating or exogenous priming agents in addition to purified recombinant L1S protein itself.…”

“…The ability of recombinant p60 to promote NK cell activity maps to a fragment termed L1S (23). In cell culture models, intact p60 protein or the L1S region indirectly stimulate activation of murine and human NK cells to secrete IFNγ due to their effects on dendritic cells (DCs) (21, 23). …”