Self MHC class I–licensed NK cells enhance adaptive CD8 T-cell viral immunity

Abstract

MHC class I (MHC I) IntroductionNatural killer (NK) cells are essential mediators of virus immunity 1 ; their deficiency in humans or depletion from mice leads to uncontrolled viral replication and poor clinical outcome. 2-4 MHC class I (MHC I) molecules, which are ligands for polymorphic human KIR and mouse Ly49 receptors, play a critical role in NK-cell activation and selftolerance. The absence of self-MHC I renders cells susceptible to NK-cell cytotoxicity. [5][6][7] Moreover, the interaction between MHC I and NK-cell inhibitory receptors is critical in NK-cell acquisition of selftolerance and functional competence. [8][9][10][11] Indeed, NK inhibitory receptor recognition of virus-infected cells displaying reduced or altered self-MHC I is a paradigm for the field. Despite this, only activation receptors have so far been shown to confer specific recognition and control of virus infection by NK cells; the significance of NK inhibitory receptors in virus recognition therefore is debated. 12 In MA/My mice and other H-2 k strains, the MHC provides vital protection against lethal murine CMV (MCMV) infection. [13][14][15] Classic genetics studies to examine MA/My virus resistance mapped genes to the MHC I D region on chromosome 17 and the NK gene complex (NKC) on chromosome 6. [15][16][17][18] Recently, we identified MHC I D k as a critical genetic factor, 19 and further demonstrated a requisite role of licensed Ly49G2 ϩ NK cells needed in MCMV resistance. 18,19 Consistent with a requirement for NK stimulatory signals, Ly49P has been shown to bind MHC I D k on infected cells displaying MCMV glycoprotein gp34. 20 Thus, virus sensing via Ly49G2 and Ly49P receptors likely combine to drive potent antiviral NK responses after MCMV infection in H-2 k mice. The intriguing finding of Babic et al recently demonstrating how MCMV gp34 associated with MHC I on infected cells may enhance interaction with NK inhibitory receptors and immune evasion strategies, further highlights that NK missing-self MHC I surveillance mechanisms contribute to virus control in vivo. 21 As major effectors in front line antiviral defenses, NK cells further impact adaptive immunity through interactions with dendritic cells (DCs). NK-DC "crosstalk" can enhance NK cytotoxicity and proliferation, sustain splenic DC subsets after virus infection, 22,23 and stimulate DC maturation and Ag-presenting functions. [22][23][24][25][26][27][28][29][30] NK cells may thus provide needed signals during NK-DC crosstalk that promote tumor-or virus-specific CD8 T-cell immunity. 23,31 In accord with this suggestion, high-affinity Ly49H recognition of MCMV m157 displayed on infected cells caused NK cells to affect the regulation of type I IFNs, DC subset retention and induction of virus-specific CD8 T-cell effectors. 22,23,26 However, rapid containment of MCMV and Ag availability via Ly49H-mediated NK responses may also inadvertently contribute to viral persistence by reducing initial CD4 and CD8 T-cell responses. 32 Whether NK inhibitory receptor recognition of virus i...

Natural Killer Cells Regulate Murine Cytomegalovirus-Induced Sialadenitis and Salivary Gland Disease

“…The timing of NK cell virus control may be critical for protection from organ damage. NK cells are innate immune responders, while MCMV-specific T cells require 4 to 5 days to develop (31,41,47). The antiviral effect of adaptive immunity in the spleen was not sufficient to protect the gland, since Rag1 mice did not succumb to secretory dysfunction after low-dose infection.…”

The NK Cell Response to Mouse Cytomegalovirus Infection Affects the Level and Kinetics of the Early CD8+T-Cell Response

“…These differences might be related to different mouse strains or the different source of virus used. In recent work, Stadnisky et al (47) showed that NK cell activation by the missing-self mechanism also resulted in faster recovery of splenic cDCs after their initial drop and in an improved CD8 ϩ T-cell response. Thus, the more robust CD8 ϩ T-cell response in mice infected with ⌬m157 virus looks like a paradox since it is accompanied by a depletion of splenic cDCs.…”

“…However, Andrews et al (3) have shown that an NK cell response mediated through Ly49H-m157 interaction limits the long-term efficacy of specific CD8 ϩ and CD4 ϩ T cells and that this is a consequence of an altered frequency and duration of infection of antigenpresenting cells. More recently, Stadnisky and colleagues (47) have demonstrated a role for inhibitory NK receptors in the CD8 ϩ T-cell response to MCMV. Although these authors did not exclude a role for MCMV-specific activating NK receptors in their model, they provided first evidence to propose that the recognition of infected cells by licensed Ly49G2 ϩ NK cells results in a faster recovery of splenic cDCs and an enhanced antigen-specific CD8 ϩ T-cell response.…”

Positive and Negative Regulation by NK Cells in Cancer

“…51 This DC lysis also reduces the various cytokines produced by DCs, which can hamper the overall immune response as well. NK cells can also promote DCs through IFNγ production, 52 CD40-CD40L interaction, 53 or GM-CSF production. Thus, a number of pathways and mechanisms exist for NK–DC interactions and reciprocal regulation of both populations during immune challenge.…”