Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo

Babić, Marina; Pyzik, Michał; Zafirova, Biljana; Mitrović, Maja; Butorac, Višnja; Lanier, Lewis L.; Krmpotić, Astrid; Vidal, Silvia M.; Jonjić, Stipan

doi:10.1084/jem.20100921

Cited by 74 publications

(84 citation statements)

References 57 publications

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“…1C). We selected these three strains because past work using depleting Abs against NK cells demonstrated that NK cell function was critical for controlling MCMV infection in all three strains (34)(35)(36)(37).…”

Section: Control Of MCMV Infection Is Not Dependent On Ncr1mentioning

confidence: 99%

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

Glasner¹,

Šimić

Miklić

et al. 2015

The Journal of Immunology

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NK cells kill various cells using activating receptors, such as the natural cytotoxicity receptors (NCRs). NKp46 is a major NCR and is the only NCR expressed in mice (denoted Ncr1). Using Ncr1-deficient mice (Ncr1gfp/pfp) we demonstrated that Ncr1 controls various pathologies, and that in its absence Ncr1-related functions are impaired. In 2012, another Ncr1-related mouse was generated, named Noé, in which a random mutation, W32R, in position 32, impaired the Ncr1-Noé cell surface expression. Interestingly, in the Noé mice, Ncr1-dependent deficiencies were not observed. Additionally, the Noé-NK cells were hyperactivated, probably due to increased Helios expression, and the Noé mice demonstrate increased clearance of influenza and murine CMV. In contrast, in the Ncr1gfp/pfp mice infection with influenza was lethal and we show in the present study no difference in murine CMV infection between Ncr1gfp/pfp and wild-type (WT) mice. Because the foremost difference between the Noé and Ncr1gfp/gfp mice is the presence of a mutated Ncr1-Noé protein, we studied its properties. We show that Ncr1-Noé and various other Ncr1 mutants in position 32 can be expressed on the surface, albeit slowly and unstably, and that ligand recognition and function of the various Ncr1-Noé is similar to the WT Ncr1. We further show that the glycosylation pattern of Ncr1-Noé is aberrant, that the Ncr1-Noé proteins accumulate in the endoplasmic reticulum, and that the expression of Ncr1-Noé proteins, but not WT Ncr1, leads to increased Helios expression. Thus, we suggest that the NK hyperactivated phenotype observed in the Noé mice might result from the presence of the Ncr1-Noé protein.

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Section: Control Of MCMV Infection Is Not Dependent On Ncr1mentioning

confidence: 99%

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

Glasner¹,

Šimić

Miklić

et al. 2015

The Journal of Immunology

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“…One of their central effects is the lysis of infected host cells. This has been best demonstrated for infections with viruses that up-or downregulate activating or inhibitory NK cell receptors or encode NK cell-activating ligands in their genome (2,37,38,40,71). Several studies suggested that NK cells also exert cytolytic effects against host cells infected with nonviral pathogens (1,47,53,55,74).…”

mentioning

confidence: 99%

Leishmania-Infected Macrophages Are Targets of NK Cell-Derived Cytokines but Not of NK Cell Cytotoxicity

et al. 2011

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“…Similar to Ly49H-Ly49I/C dichotomy, the recognition of m04/ gp34-H-2D k by the activating Ly49L/D2/P1 and the inhibitory Ly49A receptors was described (18). In this case as well, the direct involvement of Ly49A in recognition of m04/gp34-H-2D k was difficult to assess due to the strong affinity of the receptor to MHC-I.…”

mentioning

confidence: 89%

“…Viral titers were assessed 3, 4, or 6 d p.i. -expressing 2B4 reporter cells were previously described (10,18,22).…”

Section: Virus Stocks and Mouse Infectionsmentioning

confidence: 99%

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Viral MHC Class I–like Molecule Allows Evasion of NK Cell Effector Responses In Vivo

Pyzik

Dumaine

Charbonneau

et al. 2014

The Journal of Immunology

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The outcome of mouse CMV (MCMV) infection varies among different inbred mouse strains depending on NK cell effector functions governed through recognition receptor triggering. NK cells from different mouse strains possess diverse repertoires of activating or inhibitory Ly49 receptors, which share some of their polymorphic MHC class I (MHC-I) ligands. By examining the NK cell response to MCMV infection in novel BALB substrains congenic for different MHC (or H-2 in mice) haplotypes, we show that recognition of viral MHC-I–like protein m157 by inhibitory Ly49C receptor allows escape from NK cell control of viral replication. Dominant inhibition by Ly49C bound to self–H-2b encoded MHC-I molecules masks this effect, which only becomes apparent in distinct H-2 haplotypes, such as H-2f. The recognition of m157-expressing cells by Ly49C resulted in both decreased NK cell killing in vitro and reduced rejection in vivo. Further, control of infection with m157-deletant (Δm157) MCMV was improved in mice carrying H-2 molecules unrecognized by Ly49C but allowing expansion of NK cell effectors expressing activating Ly49L receptors. Hence, our study is the first, to our knowledge, to demonstrate that MHC-I mimicry strategies used by MCMV to avoid NK cell control are biologically relevant during in vivo viral infection. Of value for human studies is that only a few genetic assortments conditional on the repertoires of viral MHC-I–like proteins/host NK receptors/MHC haplotypes should allow efficient protection against CMV infection.

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Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo

Abstract: Natural killer cell recognition of “missing self” contributes meaningfully to control of mouse cytomegalovirus infection in vivo.

Cited by 74 publications

References 57 publications

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

Leishmania-Infected Macrophages Are Targets of NK Cell-Derived Cytokines but Not of NK Cell Cytotoxicity

Viral MHC Class I–like Molecule Allows Evasion of NK Cell Effector Responses In Vivo

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