The Immune Evasion Paradox: Immunoevasins of Murine Cytomegalovirus Enhance Priming of CD8 T Cells by Preventing Negative Feedback Regulation

Böhm, Verena; Simon, Christian O.; Podlech, J; Seckert, Christof K.; Gendig, Dorothea; Deegen, Petra; Gillert-Marien, Dorothea; Lemmermann, Niels A. W.; Holtappels, Rafaela; Reddehase, Matthias J.

doi:10.1128/jvi.01510-08

Cited by 66 publications

(89 citation statements)

References 70 publications

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“…3B) is in line with this hypothesis. CD8 depletion experiments performed by Böhm et al (84) did not substantially reduce viral gene expression in draining LNs of MCMV-infected mice, indicating that the bulk of the viral Ag is produced in other cell types of secondary lymphoid organs, which is in agreement with our data. It might be worth reexamining the MCMV-infected cell types in LNs and spleen using histochemical techniques to learn which cells provide the viral Ag for priming of CD8 + T cells.…”

Section: Discussionsupporting

confidence: 83%

“…Furthermore, the CD8a 2 DCs may be rather important for stimulating CD4 + T cell help and play a minor role in priming of the CD8 + T cell response (4,5). Second, Böhm et al (84) reported that CD8 + T cell priming is less efficient after infection with DvRAP mutants and explained this with a negative feedback reaction of newly primed CD8 + T cells, leading to the rapid elimination of infected cells in the LN, limiting further supply of viral Ags. The somewhat smaller T cell response that we observed after infection with the DvRAP mutants can be explained by this "immune evasion paradox" described by Bö hm et al (84).…”

Section: Discussionmentioning

confidence: 99%

“…Second, Böhm et al (84) reported that CD8 + T cell priming is less efficient after infection with DvRAP mutants and explained this with a negative feedback reaction of newly primed CD8 + T cells, leading to the rapid elimination of infected cells in the LN, limiting further supply of viral Ags. The somewhat smaller T cell response that we observed after infection with the DvRAP mutants can be explained by this "immune evasion paradox" described by Bö hm et al (84). Moreover, if we assume that the small fraction of infected CD8a 2 DCs (Fig.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…As shown in Fig. 2A by the time course of viral replication in the recipients' lungs, mutant virus replicated like WT virus only in the first 2 weeks, which is consistent with unaltered replicative fitness in the absence of immune cells (4). In contrast, significantly more-efficient control of the .…”

mentioning

confidence: 67%

Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

Böhm

Seckert

Simon

et al. 2009

J Virol

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CD8 T cells control cytomegalovirus (CMV) infection in bone marrow transplantation recipients and persist in latently infected lungs as effector memory cells for continuous sensing of reactivated viral gene expression.Here we have addressed the question of whether viral immunoevasins, glycoproteins that specifically interfere with antigen presentation to CD8 T cells, have an impact on viral latency in the murine model. The data show that deletion of immunoevasin genes in murine CMV accelerates the clearance of productive infection during hematopoietic reconstitution and leads to a reduced latent viral genome load, reduced latency-associated viral transcription, and a lower incidence of recurrence in lung explants.Establishment of latency after clearance of acute infection and the potential to reactivate to recurrent infection are key features of herpesvirus pathogenicity (41). Cytomegaloviruses (CMVs) are usually well controlled by the immune system and cause acute as well as recurrent disease mainly in the immunocompromised or immunologically immature host. Recipients (R) of bone marrow transplantation (BMT) are at risk of reactivating intrinsic human CMV (hCMV) or of becoming infected by reactivating donor (D)-derived hCMV transmitted with the transplant or of both (constellations, respectively) (9). Clinical studies (32, 38) and experimental studies of the murine model of infection with murine CMV (mCMV) (18; reviewed in reference 16) have consistently shown that timely endogenous lymphohematopoietic reconstitution of antiviral CD8 T cells is decisive for coping with CMV infection after BMT. Accordingly, preemptive immunotherapy with antiviral CD8 T cells proved to be a promising approach with the murine model (3,14,35,36,44) and in clinical trials (6,27,40). Both viruses hCMV and mCMV express proteins, so-called immunoevasins, that interfere with the major histocompatibility complex class I pathway of antigen presentation to CD8 T cells (reviewed in reference 33). Whereas many studies have demonstrated the efficacy of immunoevasins in inhibiting the cell surface presentation of antigenic peptides in infected cells in vitro, these molecules do not prevent (11,19,26) but rather enhance (4) the priming of viral epitope-specific CD8 T cells, and their role and relevance in viral pathogenesis in vivo are a currently discussed issue (8). Obviously, research on the in vivo function of immunoevasins by using viral immunoevasin gene deletion mutants can be accomplished only using animal models, and the murine model is well established. Although the detailed molecular modes of action differ between the immunoevasins of hCMV and mCMV, the biological outcome in

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“…In the MCMV model, evasins interfere with antiviral protection through certain virus-specific T cells (62,63) and enhance viral latency (64), in the face of a paradoxically increased T cell response that is likely due to more efficient cross-presentation of viral Ag (65). In a rhesus macaque model, deletion of US2-11 does not alter the course of primary CMV infection but prevents superinfection of CMV-positive animals (66).…”

Section: Discussionmentioning

confidence: 99%

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

Ameres

Besold

Plachter

et al. 2014

The Journal of Immunology

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Immunoevasive proteins (“evasins”) of human CMV (HCMV) modulate stability and localization of MHC class I (MHC I) molecules, and their supply of antigenic peptides. However, it is largely unknown to what extent these evasins interfere with recognition by virus-specific CD8 T cells. We analyzed the recognition of HCMV-infected cells by a panel of CD8 T cells restricted through one of nine different MHC I allotypes. We employed a set of HCMV mutants deleted for three or all four of the MHC I modulatory genes US2, US3, US6, and US11. We found that different HCMV evasins exhibited different allotype-specific patterns of interference with CD8 T cell recognition of infected cells. In contrast, recognition of different epitopes presented by the same given MHC I allotype was uniformly reduced. For some allotypes, single evasins largely abolished T cell recognition; for others, a concerted action of evasins was required to abrogate recognition. In infected cells whose Ag presentation efficiency had been enhanced by IFN-γ pretreatment, HCMV evasins cooperatively impared T cell recognition for several different MHC I allotypes. T cell recognition and MHC I surface expression under influence of evasins were only partially congruent, underscoring the necessity to probe HCMV immunomodulation using specific T cells. We conclude that the CD8 T cell evasins of HCMV display MHC I allotype specificity, complementarity, and cooperativity.

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The Immune Evasion Paradox: Immunoevasins of Murine Cytomegalovirus Enhance Priming of CD8 T Cells by Preventing Negative Feedback Regulation

Cited by 66 publications

References 70 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

Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

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