Expansion and Protection by a Virus-Specific NK Cell Subset Lacking Expression of the Inhibitory NKR-P1B Receptor during Murine Cytomegalovirus Infection

Abstract

NK cells play a major role in immune defense against human and murine CMV (MCMV) infection. Although the MCMV genome encodes for MHC class I–homologous decoy ligands for inhibitory NK cell receptors to evade detection, some mouse strains have evolved activating receptors, such as Ly49H, to recognize these ligands and initiate an immune response. In this study, we demonstrate that approximately half of the Ly49H-expressing (Ly49H+) NK cells in the spleen and liver of C57BL/6 mice also express the inhibitory NKR-P1B receptor. During MCMV infection, the NKR-P1B−Ly49H+ NK cell subset proliferates to constitute the bulk of the NK cell population. This NK cell subset also confers better protection against MCMV infection compared with the NKR-P1B+Ly49H+ subset. The two populations are composed of cells that differ in their surface expression of receptors such as Ly49C/I and NKG2A/C/E, as well as developmental markers, CD27 and CD11b, and the high-affinity IL-2R (CD25) following infection. Although the NKR-P1B+ NK cells can produce effector molecules such as IFNs and granzymes, their proliferation is inhibited during infection. A similar phenotype in MCMV-infected Clr-b–deficient mice, which lack the ligand for NKR-P1B, suggests the involvement of ligands other than the host Clr-b. Most interestingly, genetic deficiency of the NKR-P1B, but not Clr-b, results in accelerated virus clearance and recovery from MCMV infection. This study is particularly significant because the mouse NKR-P1B:Clr-b receptor:ligand system represents the closest homolog of the human NKR-P1A:LLT1 system and may have a direct relevance to human CMV infection.

A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

“…Notably, increased virulence of MCMV Smith in vivo has been previously observed using WT B6 mice relative to B6.Nkrp1b -/-mice (Rahim et al, 2016 On the other hand, in BALB/c and 129-strain mice, small but significant differences were observed only between the parental MCMV MW97 and Dm12 mutant viruses in vivo, with the m12 Smithrevertant virus showing an intermediate response ( Figure 7I). Interestingly, the published BALB/c and 129-strain NKR-P1A/ B/C alleles are identical.…”

Memory responses of natural killer cells

“…Similarly, NKG2D was found to amplify the proliferation of Ly49H + NK cells, but was unable to drive expansion of NK cells in the absence of Ly49H [40]. Conversely, Ly49H + NK cells that co-express the inhibitory receptors Ly49A or NKR-P1B do not expand as well as MCMV-specific NK cells that lack expression of these inhibitory receptors [39, 41], suggesting that inhibitory receptors may function as brakes to control the extent of NK cell activation and expansion. Together these studies show the importance of a co-stimulatory ‘Signal 2’ for the optimal response of NK cells to MCMV infection (Fig.…”

Natural selection for killer receptors and their MHC class I ligands: In pursuit of gene pairs that fit well in tandem

“…This effect presumably is due to self‐MHC I D b and K b ‐licensed Ly49I receptors since 5E6 does not readily bind Ly49C expressed on NK cells in B6 mice . Ly49H‐dependent sensing leading to NK cell expansion and virus control in MCMV‐infected neonates is likewise thwarted by the NKR‐P1B inhibitory NK receptor, which has Clr‐b as its self‐ligand . Interestingly, the MCMV m12 protein, another viral decoy, binds NKR‐P1B as a way to evade NK‐mediated immunity .…”

“…46 Ly49H-dependent sensing leading to NK cell expansion and virus control in MCMV-infected neonates is likewise thwarted by the NKR-P1B inhibitory NK receptor, which has Clr-b as its self-ligand. 47 Interestingly, the MCMV m12 protein, another viral decoy, binds NKR-P1B as a way to evade NK-mediated immunity. 48…”