Distinct Requirements for Activation of NKT and NK Cells during Viral Infection

Abstract

Natural killer (NK) cells are key regulators of innate defense against mouse cytomegalovirus (MCMV). Like NK cells, NKT cells also produce high levels of IFNγ rapidly after MCMV infection. However, whether similar mechanisms govern activation of these two cell-types, and the significance of NKT cells for host resistance, remain unknown. Here we show that although both NKT and NK cells are activated via cytokines, their particular cytokine requirements differ significantly, in vitro and in vivo. IL-12 is required for NKT cell activation in vitro, but is not sufficient, while NK cells have the capacity to be activated more promiscuously in response to individual cytokines from innate cells. In line with these results, GM-CSF-derived DC activated only NK cells upon MCMV infection, consistent with their virtual lack of IL-12 production, while Flt3L-derived DC produced IL-12 and activated both NK and NKT. In vivo, NKT cell activation was abolished in IL-12−/− mice infected with MCMV, while NK cells were still activated. In turn, splenic NK cell activation was more IL-18 dependent. The differential requirements for IL-12 and IL-18 correlated with the levels of cytokine receptor expression by NK and NKT cells. Finally, mice lacking NKT cells showed reduced control of MCMV, and depleting NK cells further enhanced viral replication. Taken together, our results show that NKT and NK cells have differing requirements for cytokine-mediated activation and both can contribute non-redundantly to MCMV defense, revealing that these two innate lymphocyte subsets function together to fine-tune antiviral responses.

Activation and Function of iNKT and MAIT Cells

“…Cytokines from innate immune cells can act together with TCR signals to induce cytokine production from iNKT cells. Furthermore, apart from cognate, TCRmediated activation; there is evidence that iNKT cells from mice and humans also can be activated by cytokines from innate immune cells elicited by TLR signals and other stimuli, in a TCR-independent fashion (Holzapfel, Tyznik, Kronenberg, & Hogquist, 2014;Leite-De-Moraes et al, 1999;Nagarajan & Kronenberg, 2007;Smithgall et al, 2008;Tyznik et al, 2008;Tyznik, Verma, Wang, Kronenberg, & Benedict, 2014). In this section, we provide further details on the various modes of iNKT cell activation and the role of these cells in different infections.…”

“…4C). Other studies have provided evidence for a purely cytokine-mediated activation of iNKT cells to produce IFNγ, with no requirement for a TCR-CD1d interaction (Leite- De-Moraes et al, 1999;Nagarajan & Kronenberg, 2007;Smithgall et al, 2008;Tyznik et al, 2008Tyznik et al, , 2014Wesley, Tessmer, Chaukos, & Brossay, 2008). Furthermore, using Nur77 GFP transgenic mice, which have a reporter gene construct that indicates TCR-mediated activation, it was shown that expression of the TCR reporter occurred in vivo with microbes having foreign antigens, including S. paucimobilis and S. pneumoniae, but not with microbes lacking a foreign antigen, such as S. typhimurium and mouse cytomegalovirus (MCMV) (Holzapfel et al, 2014).…”

“…NKT1 cells are the dominant group in C57BL/6 mice in spleen and liver , and they express very high levels of the IL-12 receptor Tyznik et al, 2014). The secretion of IFNγ by NKT1 cells can be driven by IL-12, but this cytokine acts most effectively in combination with small amounts of another cytokine, either IL-18 or type I interferon .…”

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

“…Latent HCMV is present in the majority of people worldwide, but the primary infection is usually asymptomatic. The primary infection is well contained by the immune cells, such as natural killer (NK) cells and T cells, which also prevent viral reactivation from latency (1,2).Their activation depends on cross talk with dendritic cells (DC) (3,4), and this interaction plays an important role in CMV control (5)(6)(7). The direct effect of DC on viral replication remains, however, unclear.…”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…Although T cells are critical in controlling CMV latency and preventing reactivation (Hanley and Bollard 2014), a role for host NK cells has been established in the acute stages of this infection (López-Botet et al 2014;Tyznik et al 2014). This DNA virus has been present in the human population for thousands of years and as such has evolved clever mechanisms of immune evasion, while simultaneously leaving an imprint on the human genome with respect to NK cell recognition of virus (Gumá et al 2004;Vidal and Lanier 2006;Brizić et al 2014).…”