All is fair in virus-host interactions: NK cells and cytomegalovirus

Abstract

The infection of mice with mouse cytomegalovirus (MCMV) as a model of human cytomegalovirus (HCMV) infection has been particularly informative in elucidating the role of innate and adaptive immune response mechanisms during infection. Millions of years of co-evolution between cytomegaloviruses (CMV) and their hosts has resulted in numerous attempts to overwhelm each other. CMVs devote many genes to modulating the host natural killer (NK) cell response and NK cells employ many strategies to cope with CMV infection. While focusing on these attack-counterattack measures, this review will discuss several novel mechanisms of immune evasion by MCMV, the role of Ly49 receptors in mediating resistance to MCMV, and the impact of the initial NK cell response on the shaping of adaptive immunity.

Figure I

Figure 1. Specific proliferation of Ly49L⁺ NK cells correlates with virus clearance in BALB.K mice

(a) At early time points post infection (day 2), natural killer (NK) cells failed to control mouse cytomegalovirus (MCMV) infection in spite of the fact that in addition to inhibitory Ly49A receptor activating Ly49L receptor can specifically recognize infected cells via the same ligand, the H-2D^k/m04 complex. In addition, inhibitory receptors might be engaged by viral ligands, therefore ensuring the dominance of inhibition (top, left). (b) During the course of infection (day 6) NK cells expressing Ly49L specifically proliferate and concurrently increase the density of Ly49L receptor on their surface. As a consequence, activation signals prevail, resulting in the containment of viral infection at later time points (top, right). (c) A schematic representation of these events is depicted in the left lower panel.

Figure 2. MCMV escapes ‘missing self’ dependent NK cell control

Schematic representation of the results obtained by a reporter cell assay (a) and natural killer (NK) cell dependent virus control in vivo (b). MHC I expressed on target cells ligates inhibitory Ly49A receptor on reporter cells resulting in their activation as measured by GFP expression. This corresponds to in vivo tolerance of NK cells to normal cells (top). Although the infection with WT MCMV results in the downregulation of MHC I, this does not prevent the activation of Ly49A reporter cells due to the fact that m04 encoded protein rescues enough surface MHC I to restore the engagement of the receptor. This correlates with the inhibition of NK cell response in vivo and the inability of mice to control the virus in a NK cell dependent manner (middle). In the absence of m04 (infection with Δm04 MCMV) the downmodulation of MHC I is more efficient, resulting in an inability of infected cells to engage the Ly49A receptor. As a consequence, NK cells are activated in a ‘missing self’ dependent manner and control the virus (bottom).

Figure 3. Various models used in studying the impact of NK cells on shaping the adaptive immune response to MCMV

(a) In Klra8 mice (C.B6-Klra8^Cmv1-r/UwaJ; these are BALB/c congenic mice carrying the C57BL/6 Natural killer cell gene complex, and are thus positive for NK1.1 and Ly49H and resistant to MCMV (mouse cytomegalovirus) [73]) Ly49H-m157 interactions not only result in an efficient virus control at day 3 post infection but also in an accelerated CD8 T cell response (top). By contrast, in normal BALB/c mice (which are Ly49H^-) a high virus load induces a surplus of type I IFN (interferon) which affects the kinetics of the CD8⁺ T cell response (bottom) [53]. (b) In BALB.B6-CT8 mice (a BALB/c congenic mouse strain expressing NK1.1 and Ly49H and resistant to MCMV [73]) the Ly49H-m157 interaction results not only in efficient virus control but also in the depletion of infected cDCs, resulting in impaired antigen presentation and CD8⁺ T cell response. The CD8⁺ T cell response may be further suppressed by IL-10 derived from Ly49H⁺ NK cells (top). In BALB.B6-CT6 mice (a BALB/c congenic mouse strain expressing NK1.1 but not Ly49H^- that is sensitive to MCMV [73]) NK cells fail to control the virus but do preserve cDCs from depletion. This results in a more robust and prolonged CD8 T cell response (bottom) [55, 56]. (c) MCMV expressing the NKG2D ligand Rae1γ is efficiently controlled in BALB/c mice, which are otherwise sensitive to MCMV infection. This promotes the survival of cDCs and helps in establishing a level of CD8 T cell response comparable to the one in normal BALB/c mice, which cannot control the virus at early time points post infection [57]. (d) NK cells expressing Ly49G2 are efficiently licensed in R7 mice (C57L.M-H2^k – a recombinant congenic strain expressing H-2D from MA/My mice; resistant to MCMV [29]) and can mediate resistance to MCMV. This promotes a faster recovery of cDCs and an efficient CD8 response (top). In contrast, R2 mice (C57L.M-H2^k – a recombinant congenic strain expressing H-2D from C57L mice; sensitive to MCMV [29]), lacking the appropriate education ligand for Ly49G2, H-2D^k, fail to mount a proper NK cell response and thus are unable to control the virus, resulting in depletion of cDCs and an affected CD8 T cell response (bottom) [58].