Persistent Virus Infection despite Chronic Cytotoxic T-Lymphocyte Activation in Gamma Interferon-Deficient Mice Infected with Lymphocytic Choriomeningitis Virus

Bartholdy, Cecilie; Christensen, Jan Pravsgaard; Wodarz, Dominik; Thomsen, Allan Randrup

doi:10.1128/jvi.74.22.10304-10311.2000

Cited by 131 publications

(113 citation statements)

References 52 publications

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“…Therefore, a group of microchip-implanted C57BL/6 mice were infected with vaccinia virus. As reported, these mice develop strong CD8 + T cell responses, with approximately 11.5% of splenic CD8 + T cells responding to in vitro incubation with the dominant peptide, B8R [20][21][22][23][24][25][26][27] ( Figure 3A). Most relevant to the present study, the injection of 100 μg of the B8R 20-27 peptide 8 days after vaccinia infection resulted in a very rapid hypothermia ( Figure 3B), although all mice recovered.…”

Section: Figurementioning

confidence: 80%

Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology

Liu

Feuer²,

Hassett³

et al. 2006

Journal of Clinical Investigation

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CD8 + T cells play a key role in clearing primary virus infections and in protecting against subsequent challenge. The potent antiviral effects of these cells make them important components of vaccine-induced immunity and, because of this, peptide vaccines often contain epitopes designed to induce strong CD8 + T cell responses. However, the same effector functions that protect the host also can be harmful if they are not tightly regulated, and virus-specific CD8 + T cells are a frequent cause of immunopathology. Here, we report that the administration of peptide to virus-immune recipient mice can lead to the synchronous activation of preexisting virus-specific CD8 + T cells with serious, and even lethal, consequences. Mice infected with LCMV or vaccinia virus developed rapid and profound hypothermia following injection of cognate synthetic peptides, and LCMV-infected mice frequently died within hours. Detailed analyses of the LCMV infected mice revealed enterocyte apoptosis and implicated TNF produced by peptide-specific CD8 + T cells as the major mediator of disease. The caspase inhibitor zVADfmk had no demonstrable effect on the development of hypothermia, but diminished enterocyte apoptosis and greatly reduced the number of deaths. These findings, if similarly observed in patients, counsel caution when administering powerful immunogens such as peptide vaccines to individuals who may have a large preexisting pool of epitope-specific CD8 + T cells.

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Section: Figurementioning

confidence: 80%

Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology

Liu

Feuer²,

Hassett³

et al. 2006

Journal of Clinical Investigation

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“…IFN-␥ has been shown to be essential for defense against a variety of infections (9,10,24,(62)(63)(64). During LCMV infections, its role has been more controversial, with IFN-␥ reported to modestly inhibit viral replication in vitro (13) and to enhance viral clearance (65)(66)(67). We and others have shown that IFN-␣␤ are important for control of LCMV (13)(14)68).…”

Section: Discussionmentioning

confidence: 99%

A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections

Pien

Nguyen

Malmgaard

et al. 2002

The Journal of Immunology

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The kinetics of CD8 T cell IFN-γ responses as they occur in situ are defined here during lymphocytic choriomeningitis virus (LCMV) infections, and a unique mechanism for the innate cytokines IFN-αβ and IL-18 in promoting these responses is defined. Infections of mice with Armstrong or WE strains of LCMV induced an unexpectedly early day 4 IFN-γ response detectable in serum samples and spleen and liver homogenates. Production of IFN-γ was MHC class I/CD8 dependent, but did not require IL-12, NK cells, TCR-γδ T cells, MHC class II, or CD4 T cells. Peak response required specific Ag recognition, as administration of antagonist peptide partially impaired day 4 IFN-γ induction, and viral peptide stimulation enhanced CD8 T cell IFN-γ expression in culture. The IFN-γ response was associated with IL-18 and IFN-αβ expression. Furthermore, both factors augmented peptide-driven IFN-γ production in culture, and mice lacking IL-18 or IFN-αβ functions had reduced day 4 IFN-γ. Collectively, these results demonstrate that during viral infections, there is a dramatic in vivo CD8 T cell response preceding maximal expansion of these cells, and that the mechanism supporting this response is dependent on endogenous innate cytokines. Because stimulation by microbial products is linked to innate cytokine expression, the studies also suggest a pathway for precisely limiting T cell functions to times of need.

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“…Thus, as opposed to perforin, which was essential for virus control irrespective of replication rate, the importance of IFN-g varied with this viral parameter (Nansen et al 1999). However, a small in£uence was noted, and extended analysis of virus levels in LCMV Armstrong-infected IFN-g-de¢cient mice revealed that the infection was never completely controlled and signi¢-cant levels of virus could be demonstrated in spleen and lungs for months after infection (Bartholdy et al 2000). Notably, no impairment of either e¡ector or memory Tcell generation was observed in these mice as evidenced by supranormal ex vivo CTL activity and increased numbers of CTL precursors as determined by limiting dilution.…”

Section: Effector Molecules Involved In the Control Of Infection Withmentioning

confidence: 99%

“…Under these assumptions (Bartholdy et al 2000), the model predicts that the outcome of infection in IFN-g-de¢cient mice is critically dependent on the replication rate of the virus and that persistent infection in the absence of substantial immunopathology is only possible for slowly replicating strains. Moreover, in the latter situation the balance between virus load and CTL activity will settle at a new equilibrium characterized by a compensatory increase in CTL activity, which is precisely what we observe in IFN-gde¢cient mice infected with LCMV Armstrong.…”

Section: The Use Of Mathematical Modelling As a Tool To Understand T-mentioning

confidence: 99%

Host factors influencing viral persistence

Thomsen

Nansen

Andreasen

et al. 2000

Phil. Trans. R. Soc. Lond. B

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With the aim of characterizing the antiviral immune response to a non-cytocidal virus, we studied the outcome of lymphocytic choriomeningitis virus infection in a number of gene knockout mouse strains. Two virus strains di¡ering markedly in their capacity to spread and replicate inside the murine host were used. Our results reveal that very di¡erent outcomes may be observed depending on virus strain and immunocompetence of the host. Thus while CD4 + cells are not critical during the initial phase of virus control, infectious virus reappear in mice lacking CD4 + cells, B cells or CD40 ligand. Reappearance of virus is associated with impaired long-term CD8 + T-cell mediated immune surveillance, and the time to virus resurgence is inversely correlated to the replication rate of the virus. Our studies also reveal that interferon-g is a central cytokine, and depending on the rate of virus replication, mice lacking the ability to produce interferon-g may develop either a severe, mostly fatal, T-cell mediated wasting syndrome or a chronic infection characterized by long-term coexistence of antiviral cytotoxic T lymphocytes and infectious virus. Mathematical modelling indicates that these di¡erent outcomes may be explained in relatively simple mathematical terms. This suggests that modelling may be used as a means to predict critical host and virus parameters. Therefore, combining mathematical modelling with precise, quantitative, in vivo analyses looks to be a promising approach in addressing central quantitative issues in immunobiology.

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Persistent Virus Infection despite Chronic Cytotoxic T-Lymphocyte Activation in Gamma Interferon-Deficient Mice Infected with Lymphocytic Choriomeningitis Virus

Cited by 131 publications

References 52 publications

Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology

Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology

A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections

Host factors influencing viral persistence

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