Murine Model of Interstitial Cytomegalovirus Pneumonia in Syngeneic Bone Marrow Transplantation: Persistence of Protective Pulmonary CD8-T-Cell Infiltrates after Clearance of Acute Infection

Podlech, Jürgen; Holtappels, Rafaela; Pahl-Seibert, Marcus-Folker; Steffens, Hans-Peter; Reddehase, Matthias J.

doi:10.1128/jvi.74.16.7496-7507.2000

Cited by 108 publications

(160 citation statements)

References 47 publications

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“…However, it was plausible that the activated T cells accumulated in the lungs of MCMVinfected mice because of another purpose, for example, a physiological role. The experiments by Podlech et al (30) as well as our previous results (1,2) and the data presented in this study identified the powerful MCMV-amplified response potential of the pulmonary CD8 T cells. They demonstrated not only the persistence of CD8 T cells even after virus clearance, but also their antiviral effect.…”

Section: Discussionmentioning

confidence: 69%

Role of the Indigenous Microbiota in Maintaining the Virus-Specific CD8 Memory T Cells in the Lung of Mice Infected with Murine Cytomegalovirus

Tanaka

Sawamura

Satoh

et al. 2007

The Journal of Immunology

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The potent role of indigenous microbiota in maintaining murine CMV (MCMV)-specific memory T cells, which were measured by multimer staining, was investigated using germfree (GF) mice. When the BALB/c mice bred under specific pathogen-free (SPF) conditions were i.p. infected with 0.2 LD50 of MCMV, high frequencies of CD69+/CD44+ MCMV-specific CD8 T cells were noted in the lungs even at 6–12 mo after infection (11.1 ± 3.2 and 9.8 ± 0.9%, respectively). In contrast, even though the viral load and expression levels of mRNA of such cytokines as IL-2, IL-7, IL-15, and IFN-γ in the lungs of MCMV-infected GF mice were comparable to those of infected SPF mice, the frequencies of MCMV-specific CD8 T cells in the lungs of infected GF mice were kept lower than 1% at 6–12 mo after infection. In addition, the reconstitution of microbiota of MCMV-infected GF mice by orally administering a fecal suspension prepared from SPF mice restored the frequencies of both CD8+/multimer+ and CD8+/multimer− T cells to levels similar to those found in SPF mice. These results suggested the indigenous microbiota to play a crucial role in the expansion and maintenance of viral-specific CD8 memory T cells, probably by cross-reactivity between the antigenic epitope of the MCMV-specific memory T cells and the variety of peptides derived from the members of the microbiota. Such cross-reactivity may thus be a major feature of those cells.

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Section: Discussionmentioning

confidence: 69%

Role of the Indigenous Microbiota in Maintaining the Virus-Specific CD8 Memory T Cells in the Lung of Mice Infected with Murine Cytomegalovirus

Tanaka

Sawamura

Satoh

et al. 2007

The Journal of Immunology

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“…Indeed, ample evidence from immunocompromised transplant or HIV patients documents a crucial role of the immune system, particularly CD8 + T cells, in anti-CMV immunity and in controlling the virus and CMV disease in these individuals (2). In murine models, IE-1-specific CD8 + T cells protected mice from a lethal challenge dose of virus, both in acute infection and following bone marrow transplantation with simultaneous murine CMV infection (28,29). The few available human studies comparing the protective capacity of pp65-or IE-1-specific immune responses tend to be contradictory.…”

Section: Discussionmentioning

confidence: 99%

Hallmark Features of Immunosenescence Are Absent in Familial Longevity

Derhovanessian¹,

Maier

Beck

et al. 2010

The Journal of Immunology

148

111

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“…An impact of vRAPs might rather be seen in the immunocompromised host, especially in the clinically relevant situation of lymphohematopoietic reconstitution of antiviral CD8 T cells in BMT recipients. Importantly, whereas CD8 T cells can be replaced with other innate and adaptive effector cells in otherwise immunocompetent mice (20), antiviral CD8 T cells are essential for preventing CMV disease in the BMT setting (30,31). Although deletion of vRAP m152/ gp40 can also activate NK cells through expression of the activating NKG2D ligand RAE-1 (for a review, see reference 24), previous work has demonstrated that CD8 T cells outperform NK cells in controlling the in vivo replication of mCMV⌬vRAP (4).…”

mentioning

confidence: 99%

“…Here we focused on infection of the lungs, since interstitial pneumonia is a very relevant manifestation of CMV disease in BMT recipients (39) and since the lungs are a major organ site of mCMV latency after neonatal infection (2) and after experimental BMT (22,30). Figure 1 sketches the experimental protocol of syngeneic BMT (Fig.…”

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confidence: 99%

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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Murine Model of Interstitial Cytomegalovirus Pneumonia in Syngeneic Bone Marrow Transplantation: Persistence of Protective Pulmonary CD8-T-Cell Infiltrates after Clearance of Acute Infection

Cited by 108 publications

References 47 publications

Role of the Indigenous Microbiota in Maintaining the Virus-Specific CD8 Memory T Cells in the Lung of Mice Infected with Murine Cytomegalovirus

Role of the Indigenous Microbiota in Maintaining the Virus-Specific CD8 Memory T Cells in the Lung of Mice Infected with Murine Cytomegalovirus

Hallmark Features of Immunosenescence Are Absent in Familial Longevity

Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

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