Impaired Generation of Anti-AKR/Gross Murine Leukemia Virus Cytotoxic T Lymphocytes in Mice Experimentally Infected with MuLV

Coppola, Michael A.; Green, William R.; Rich, Robert F.

doi:10.1089/vim.1996.9.107

Cited by 6 publications

(1 citation statement)

References 33 publications

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“…Type-specific antiretroviral cytotoxic T-iymphocyte (GTL) responses have been described to both the exogenous FMR and to the endogenous AKR/Gross MuLV, which distinguish these two groups of MuLV. For reviews of cell-mediated immune responses to FMR MuLV, including a major H-2D''-rcstricted CTL epitope(s) located in the upstream leader sequence of gag that is shared by these retroviruses (4, 5), the reader is referred to Chesebro et al (6) and Fan (7).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape

Green

1999

Immunological Reviews

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Mouse retrovirus-induced lymphoma/leukemia and immunodeficiency are useful models for analogous human diseases. Both ecotropic (mouse tropic) and recombinant retroviruses, including the polytropic mink cytopathic focus-inducing type, have been studied for disease pathogenesis and as targets for humoral and cellular immunity, particularly cytotoxic T-lymphocyte (CTL) responses. For AKR/Gross murine leukemia viruses (MuLV) we have defined an immunodominant CTL epitope in the p 15E transmembrane anchor envelope protein and three minor/subdominant epitopes. Evidence is presented for retroviral escape from CTL by selection following genetic recombination and point mutation both within and outside CTL epitope sequences, and via endogenous retrovirus-infected cell downregulation of the generation of anti-AKR/Gross MuLV CTL. As demonstrated in vivo in naturally occurring non-responder strains by adoptive transfer, and in vitro by cell-mixing experiments, a central non-responsiveness mechanism appears to be peripheral inhibition mediated by infected cells expressing MHC-presented viral peptides. Such inhibition requires Fas expression by antiviral T cells; occurs upon TCR-mediated recognition of virus-infected, Fas ligand-expressing "veto" cells; and apparently leads to an antigen-specific form of activation-induced cell death of T cells. In the LP-BM5 MuLV isolate that causes murine AIDS (MAIDS) retroviral variation also leads to CTL escape--the BM5-helper virus has altered forms of the immunodominant and two minor/subdominant epitopes. In contrast, a novel immunodominant CTL epitope is recognized by MAIDS resistant, but not MAIDS-susceptible, strains. This epitope is uniquely encoded in an alternative translational reading frame of the viral gag gene. It also appears that the LP-BM5 MuLV have co-opted the cells of the immune system for retroviral pathogenesis--CD40/CD40L (CD154) interactions are required both for the initiation and progression of MAIDS.

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Section: Introductionmentioning

confidence: 99%

Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape

Green

1999

Immunological Reviews

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The Role of Proximal and Distal Sequence Variations in the Presentation of an Immunodominant CTL Epitope Encoded by the Ecotropic AK7 MuLV

Kim¹,

Green²

1997

Virology

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An emv-14-derived, replication-competent ecotropic murine leukemia virus [MuLV], designated AK7, was previously cloned from the AKXL-5 recombinant inbred mouse strain and partially characterized. While genetically encoding for an envelope-derived immunodominant CTL epitope [KSPWFTTL] located in the transmembrane region of p15TM, this virus, unlike the emv-11-derived virus AKR623, fails to be efficiently recognized by AKR/Gross MuLV-specific cytotoxic T lymphocytes [CTL]. AK7 thus provides the opportunity to study the role of retroviral sequence variations that are located outside of the immunodominant epitope as a mechanism of escape from CTL-mediated immune surveillance. In an attempt to identify which region[s] of the AK7 genome could account for its ability to evade efficient recognition by AKR/Gross MuLV-specific CTL, we have constructed recombinant murine retroviruses. The direct influence of a sequence variation twelve amino acids N-terminal to KSPWFTTL was explored with the use of chimeric viruses and determined not to significantly impair the presentation of KSPWFTTL to AKR/Gross MuLV-specific CTL. The long terminal repeat [LTR] derived from the AK7 virus, which possesses only one copy of the 99-base pair transcriptional enhancer in the U3 region, in contrast to AKR623 that possesses two copies of the tandem direct repeat enhancers, was also analyzed for its influence on the presentation of KSPWFTTL. Interestingly, our data indicate that the enhancer region derived from AK7 negatively influences the presentation of KSPWFTTL in the context of a recombinant AKR623 virus.

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High Levels of IL-4 and IL-10 mRNA and Low Levels of IL-2, IL-9 and IFN-γ mRNA in MuLV-Induced Lymphomas

et al. 1999

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The expression of cytokines may influence the development of lymphoma in retrovirally infected animals in at least two ways: (1) cytokines in the tumor environment may stimulate the proliferation of tumor cells and/or (2) cytokines in the tumor environment may diminish the cell-mediated antitumor immune response. To evaluate these possibilities, a semiquantitative RT-PCR approach was utilized to permit a broad screening of cytokine mRNAs in a large number of tissue samples. Examination of MuLV-induced end-stage lymphomas revealed the absence of mRNA for cytokines known to stimulate the proliferation of T cells (i.e., IL-2, IL-9), the absence of mRNA for cytokines known to enhance cell-mediated antitumor immune responses (i.e., IL-2, IFNgamma), and the presence of mRNA for cytokines known to diminish such responses (i.e., IL-4, IL-10). Similar patterns of cytokine mRNA expression were detected in tumor-derived cell lines. Spleen and thymus from animals collected longitudinally during infection and from age-matched uninfected mice also demonstrated a similar pattern, except that IFNgamma mRNA was readily detectable. These findings do not support the hypothesis that the developing tumor depends on cytokines to provide proliferative signals. The findings suggest that cytokines in the immediate environment of the lymphoma support tumor development by acting to diminish an effective antitumor immune response.

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Impaired Generation of Anti-AKR/Gross Murine Leukemia Virus Cytotoxic T Lymphocytes in Mice Experimentally Infected with MuLV

Cited by 6 publications

References 33 publications

Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape

Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape

The Role of Proximal and Distal Sequence Variations in the Presentation of an Immunodominant CTL Epitope Encoded by the Ecotropic AK7 MuLV

High Levels of IL-4 and IL-10 mRNA and Low Levels of IL-2, IL-9 and IFN-γ mRNA in MuLV-Induced Lymphomas

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