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

Mitrović, Maja; Arapović, Maja; Jordan, Stefan; Fodil-Cornu, Nassima; Ebert, Stefan; Vidal, Silvia M.; Krmpotić, Astrid; Reddehase, Matthias J.; Jonjić, Stipan

doi:10.1128/jvi.06042-11

Cited by 79 publications

(130 citation statements)

References 54 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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“…Thus, treatment with the anti-CD25 antibody may have also depleted NK cells, whereas in our approach, only Foxp3 ϩ Tregs were ablated. Depletion of NK cells has been shown to enhance mCMV titers and mCMV-specific T cell responses during acute mCMV infection (22)(23)(24)(25)(26), which might be the reason for the strong effect reported by Arens et al (20). Unlike with mCMV, the expansion of Tregs has been found in mice infected with other herpesviruses, like herpes simplex virus (HSV) (12,27).…”

Section: Fig 3 Mcmv-specific Cd8mentioning

confidence: 99%

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

Duppach

Francois

Joedicke

et al. 2014

J Virol

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It is still unclear whether expanded and activated regulatory T cells (Tregs) in chronic viral infections can influence primary immune responses against superinfections with unrelated viruses. Expanded Tregs found in the spleens of chronically Friend virus (FV)-infected mice decreased murine cytomegalovirus (mCMV)-specific CD8؉ T cell responses during acute mCMV superinfection. This suppression of mCMV-specific T cell immunity was found only in organs with FV-induced Treg expansion. Surprisingly, acute mCMV infection itself did not expand or activate Tregs. P revious infections can influence the immune response to infections with unrelated pathogens, which is called heterologous immunity (1, 2). This phenomenon has been found in closely related and completely unrelated viral infections in humans and in mouse models (3). To date, limited information is available as to whether virus-expanded regulatory T cells (Tregs) in a chronically infected host play a role in heterologous immunity. In this study, we investigated the influence of Friend virus (FV)-expanded Tregs on the primary murine cytomegalovirus (mCMV)-specific CD8 ϩ T cell response during an acute mCMV superinfection.We first confirmed the expansion of Tregs during FV infection by determining the number of Tregs in chronically FV-infected mice in different organs ( Fig. 1a) (4, 5). C57BL/6 mice (males, 8 to 9 weeks old) were infected intravenously with 40,000 spleen focusforming units (SFFU) of FV, and CD4 ϩ Foxp3 ϩ Tregs were measured at day 42 postinfection (6, 7). Significantly enhanced percentages (not shown) and absolute numbers of Tregs were found in the spleens but not in the livers and peritoneal exudate cells (PECs) of chronically FV-infected mice compared to results for naive, age-matched controls (Fig. 1a). FV-expanded Tregs had an activated and differentiated phenotype (CD43 ϩ CD69 ϩ and KLRG-1 ϩ ), in contrast to Tregs from uninfected mice at day 10 and day 42 after FV infection ( Fig. 1c and reference 8, respectively).To investigate whether mCMV infection also induces an expansion of Tregs, naive mice were infected intraperitoneally with 5 ϫ 10 4 PFU of mCMV (Smith strain [7]) and CD4 ϩ Foxp3 ϩ Tregs were analyzed at day 10 postinfection in the spleen, liver, and salivary gland, sites where mCMV replicates (9). Surprisingly, no expansion or activation of Tregs was found in the spleens of acutely mCMV-infected mice, in contrast to what is described for FV or lymphocytic choriomeningitis virus (LCMV) infection (Fig. 1b and c) (10-12). Additionally, no expansion of the V␤5 ϩ CD4 ϩ Foxp3 ϩ Tregs, which recognize self-superantigens expressed by endogenous mouse mammary tumor virus, were detectable in mCMV-infected mice (8, 10, 11; data not shown). Furthermore, Tregs from mCMV-infected mice displayed the same phenotype as Tregs from naive animals (Fig. 1c). This was also the case for later time points after mCMV infection (Ͼ10 days postinfection) (data not shown), indicating that mCMV does not induce Treg responses in C57BL/6 mice.Tregs in influen...

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“…Even though NK cell killing of MCMV-infected cells allows for rapid control of viral spread, it reduces the availability of APC and limits the length and potency of virus-specific adaptive T cell responses as evidenced by Andrews et al (34) or Mitrović et al (35). Therefore, strong innate immune responses might have detrimental effects on long lasting adaptive immunity.…”

Section: Discussionmentioning

confidence: 99%

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

Cited by 79 publications

References 54 publications

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

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

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

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

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

Cited by 79 publications

References 54 publications

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

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

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

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

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Product

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