Viral Interference with B7-1 Costimulation: A New Role for Murine Cytomegalovirus Fc Receptor-1

Mintern, Justine D.; Klemm, Elizabeth J.; Wagner, Markus; Paquet, Marie Eve; Napier, Melanie D.; Kim, You-Me; Koszinowski, Ulrich H.; Ploegh, Hidde L.

doi:10.4049/jimmunol.177.12.8422

Cited by 56 publications

(49 citation statements)

References 64 publications

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“…2B). Because peptide-pulsed, MCMV-infected DCs were able to rescue proliferation of specific T cells (data not shown), prevention of adequate presentation of the endogenously generated epitope by viral MHC I immune evasion proteins is the most likely explanation for this observation, although there might be a contribution of other immunomodulatory mechanisms of MCMV (18,20,44,45). The result of the in vitro experiment was contrasted by efficient generation of gB 498 -specific CD8 + T cells in vivo after infection of B6 mice with MCMV-IE1gB (Fig.…”

Section: Mcmv-infected Dcs Are Incapable Of Inducing Proliferation Ofmentioning

confidence: 97%

“…6A, 6B). Third, because MCMV interferes not just with Ag presentation, but also with costimulation by downregulating CD40, CD80, and CD86 on infected APCs (43,44,46), it is possible that a second layer of defense impairs direct priming even when Ag presentation is restored. Further research is required to investigate whether one or several of the proposed mechanisms can explain the observed data.…”

Section: Discussionmentioning

confidence: 99%

“…On the contrary, there are results that indicated some leakiness in the functions of vRAPs (40)(41)(42). However, even if infected DCs retain a residual capacity for Ag presentation, a series of additional viral mechanisms ranging from downregulation of costimulatory molecules over changes in the secretion of chemokines and cytokines to the inhibition of migration and maturation may severely impair DC functions (17,18,(43)(44)(45)(46)(47)(48)(49)(50)). Yet again, there are studies that report on host countermeasures that retain the function of DCs after CMV infection (51)(52)(53).…”

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confidence: 90%

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Priming of CD8+ T Cells against Cytomegalovirus-Encoded Antigens Is Dominated by Cross-Presentation

Busche

Jirmo

Welten

et al. 2013

The Journal of Immunology

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CMV can infect dendritic cells (DCs), and direct Ag presentation could, therefore, lead to the priming of CMV-specific CD8+ T cells. However, CMV-encoded immune evasins severely impair Ag presentation in the MHC class I pathway; thus, it is widely assumed that cross-presentation drives the priming of antiviral T cells. We assessed the contribution of direct versus cross priming in mouse CMV (MCMV) infection using recombinant viruses. DCs infected with an MCMV strain encoding the gB498 epitope from HSV-1 were unable to stimulate in vitro naive gB498-specific CD8+ T cells from TCR transgenic mice. Infection of C57BL/6 mice with this recombinant virus led, however, to the generation of abundant numbers of gB498-specific T cells in vivo. Of the DC subsets isolated from infected mice, only CD8α+ DCs were able to stimulate naive T cells, suggesting that this DC subset cross-presents MCMV-encoded Ag in vivo. Upon infection of mice with MCMV mutants encoding Ag that can either be well or hardly cross-presented, mainly CD8+ T cells specific for cross-presented epitopes were generated. Moreover, even in the absence of immune evasion genes interfering with MHC class I–mediated Ag presentation, priming of T cells to Ag that can only be presented directly was not observed. We conclude that the host uses mainly DCs capable of cross-presentation to induce the CMV-specific CD8+ T cell response during primary, acute infection and discuss the implications for the development of a CMV vaccine.

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Section: Mcmv-infected Dcs Are Incapable Of Inducing Proliferation Ofmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

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Priming of CD8+ T Cells against Cytomegalovirus-Encoded Antigens Is Dominated by Cross-Presentation

Busche

Jirmo

Welten

et al. 2013

The Journal of Immunology

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“…HIV is highly efficient at evading immune responses through mechanisms such as modulation of MHC class II presentation (33) and downregulation of MHC class I molecules (3,(33)(34)(35). Many other viral immune evasion strategies are also described (36)(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules

D’Orsogna

Heuvel

Meer-Prins

et al. 2012

The Journal of Immunology

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Viral infection is a major cause of morbidity and mortality, and there are few therapeutic options available to augment a virus-specific T cell response. Although allo-HLA cross-reactivity from virus-specific memory T cells is common, it is unclear whether priming with specific allogeneic cells could conversely elicit a viral peptide/self-HLA restricted cytotoxic T cell response in humans. First, we used the previously described allo-HLA-B*44:02 cross-reactivity of EBV peptide/HLA-B8 restricted T cells, to determine whether allogeneic HLA stimulation can elicit a cytolytic immune response against EBV. HLA-B8+ HLA-B44− EBV-seropositive PBMCs were stimulated with either HLA-B*44:02+ or HLA-B*44:03+ mismatched irradiated PBMCs in a 7–10 d MLR. The allo-HLA stimulated responder cells were then evaluated for cytotoxicity using EBV peptide loaded autologous target cells and unloaded HLA-B8+ EBV LCL target cells. PBMCs from EBV-seropositive donors gained EBV-specific cytolytic effector function following specific allo-HLA stimulation. Finally, we also elicited cytolytic CMV-specific responses using specific allogeneic cell stimulation, to confirm that this technique can be used to elicit viral peptide/self-HLA restricted responses even from nonpublic TCR responses. Allogeneic cell stimulation used as a cell therapy may be a potential tool to augment an antiviral T cell response in patients with EBV or CMV infection.

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“…Furthermore, our recent unpublished data indicate that m138/fcr-1 might also target some RAE-1 family members for down-modulation (J. Arapovic, unpublished). In addition to NKG2D ligands, m138/fcr-1 is able to down-regulate the costimulatory molecule B7-1 (CD80) [64] and thus has a strong impact on the T cell response since it impairs the ability of DCs to activate CD8 + T cells. This might be an explanation for the much broader in vivo attenuation of the MCMV mutant lacking m138/fcr-1 as compared to the mutant viruses lacking other NKG2D ligand regulators.…”

Section: Down-modulation Of Surface Resident Mult-1: a Joint Evort Ofmentioning

confidence: 99%

Murine cytomegalovirus regulation of NKG2D ligands

Lenac

Arapović

Traven

et al. 2008

Med Microbiol Immunol

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Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes morbidity risk in immunologically suppressed and immunodeWcient patients including congenital infections. Approaches to curb the consequences of HCMV infections are restricted by a lack of complete understanding of viral pathogenesis. The infection of mice with murine cytomegalovirus (MCMV) as a model of HCMV infection has been particularly useful in elucidating the role of innate and adaptive immune response mechanisms. A large number of cytomegalovirus genes modulate the innate and the adaptive host immune response. The products of several MCMV genes are involved in subverting the natural killer (NK) cell response by down-modulating cellular ligands for the NKG2D receptor expressed on NK cells and CD8 + T cells. Mutant viruses lacking these immunoevasion genes are attenuated with respect to virus growth in vivo. Given the importance of the NKG2D receptor in controlling both NK-and T cell-mediated immunity, it is of tremendous importance to understand the molecular mechanisms and consequences of viral regulation of the NKG2D ligands.

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Viral Interference with B7-1 Costimulation: A New Role for Murine Cytomegalovirus Fc Receptor-1

Cited by 56 publications

References 64 publications

Priming of CD8+ T Cells against Cytomegalovirus-Encoded Antigens Is Dominated by Cross-Presentation

Priming of CD8+ T Cells against Cytomegalovirus-Encoded Antigens Is Dominated by Cross-Presentation

Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules

Murine cytomegalovirus regulation of NKG2D ligands

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