Fas-dependent CD4(+) cytotoxic T-cell-mediated pathogenesis during virus infection

AJ Zajac, Daniel Quinn, PL Cohen, JA Frelinger

    Research output: Contribution to journalArticle

    52 Citations (Scopus)

    Abstract

    beta(2)-Microglobulin-deficient (beta(2)m(-)) mice generate a CD4(+) major histocompatibility complex class II-restricted cytotoxic (CTL) response following infection with lymphocytic choriomeningitis (LCM) virus (LCMV). We have determined the cytotoxic mechanism used by these CD4(+) CTLs and have examined the role of this cytotoxic activity in pathogenesis of LCM disease in beta(2)m(-) mice. Lysis of LCMV-infected target cells by CTLs form beta(2)m(-) mice is inhibited by addition of soluble Fas-Ig fusion proteins or by pretreatment of the CTLs with the protein synthesis inhibitor emetime. In addition, LCMV-infected cell lines that are resistant to anti-Fas-induced apoptosis are refractory to lysis by these virus-specific CD4(+) CTLs. These data indicate that LCMV-specific CD4(+) CTLs from beta(2)m(-) mice use a Fas-dependent lytic mechanism. Intracranial (i.c.) infection of beta(2)m(-) mice with LCMV results in loss of body weight. Fas-deficient beta(2)m(-).lpr mice develop a similar wasting disease following i.c. infection. This suggests that Fas-dependent cytotoxicity is not required for LCMV-induced weight loss. A potential mediator of this chronic wasting disease is tumor necrosis factor (TNF)-alpha, which is produced by LCMV-specific CD4(+) CTLs. In contrast to LCMV-induced weight loss, lethal LCM disease in beta(2)m(-) mice is dependent on Fas-mediated cytotoxicity. Transfer of immune splenocytes from LCMV-infected beta(2)m(-) mice into irradiated infected beta(2)m(-) mice results in death of recipient animals. In contrast, transfer of these splenocytes into irradiated infected beta(2)m(-).lpr mice does not cause death. Thus a role for CD4(+) T-cell-mediated cytotoxicity in virus-induced immunopathology has now been demonstrated.
    LanguageEnglish
    Pages14730-14735
    JournalPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Volume93
    Issue number25
    DOIs
    Publication statusPublished - Dec 1996

    Fingerprint

    Lymphocytic choriomeningitis virus
    Virus Diseases
    T-Lymphocytes
    Lymphocytic Choriomeningitis
    Weight Loss
    Chronic Wasting Disease
    Infection
    Wasting Syndrome
    Viruses
    beta 2-Microglobulin
    Protein Synthesis Inhibitors
    Major Histocompatibility Complex
    Cause of Death
    Tumor Necrosis Factor-alpha
    Body Weight
    Apoptosis
    Cell Line

    Cite this

    @article{24f1b5d9b08544ceb967e8ff029d7e6f,
    title = "Fas-dependent CD4(+) cytotoxic T-cell-mediated pathogenesis during virus infection",
    abstract = "beta(2)-Microglobulin-deficient (beta(2)m(-)) mice generate a CD4(+) major histocompatibility complex class II-restricted cytotoxic (CTL) response following infection with lymphocytic choriomeningitis (LCM) virus (LCMV). We have determined the cytotoxic mechanism used by these CD4(+) CTLs and have examined the role of this cytotoxic activity in pathogenesis of LCM disease in beta(2)m(-) mice. Lysis of LCMV-infected target cells by CTLs form beta(2)m(-) mice is inhibited by addition of soluble Fas-Ig fusion proteins or by pretreatment of the CTLs with the protein synthesis inhibitor emetime. In addition, LCMV-infected cell lines that are resistant to anti-Fas-induced apoptosis are refractory to lysis by these virus-specific CD4(+) CTLs. These data indicate that LCMV-specific CD4(+) CTLs from beta(2)m(-) mice use a Fas-dependent lytic mechanism. Intracranial (i.c.) infection of beta(2)m(-) mice with LCMV results in loss of body weight. Fas-deficient beta(2)m(-).lpr mice develop a similar wasting disease following i.c. infection. This suggests that Fas-dependent cytotoxicity is not required for LCMV-induced weight loss. A potential mediator of this chronic wasting disease is tumor necrosis factor (TNF)-alpha, which is produced by LCMV-specific CD4(+) CTLs. In contrast to LCMV-induced weight loss, lethal LCM disease in beta(2)m(-) mice is dependent on Fas-mediated cytotoxicity. Transfer of immune splenocytes from LCMV-infected beta(2)m(-) mice into irradiated infected beta(2)m(-) mice results in death of recipient animals. In contrast, transfer of these splenocytes into irradiated infected beta(2)m(-).lpr mice does not cause death. Thus a role for CD4(+) T-cell-mediated cytotoxicity in virus-induced immunopathology has now been demonstrated.",
    author = "AJ Zajac and Daniel Quinn and PL Cohen and JA Frelinger",
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    doi = "10.1073/pnas.93.25.14730",
    language = "English",
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    Fas-dependent CD4(+) cytotoxic T-cell-mediated pathogenesis during virus infection. / Zajac, AJ; Quinn, Daniel; Cohen, PL; Frelinger, JA.

    In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol. 93, No. 25, 12.1996, p. 14730-14735.

    Research output: Contribution to journalArticle

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    N2 - beta(2)-Microglobulin-deficient (beta(2)m(-)) mice generate a CD4(+) major histocompatibility complex class II-restricted cytotoxic (CTL) response following infection with lymphocytic choriomeningitis (LCM) virus (LCMV). We have determined the cytotoxic mechanism used by these CD4(+) CTLs and have examined the role of this cytotoxic activity in pathogenesis of LCM disease in beta(2)m(-) mice. Lysis of LCMV-infected target cells by CTLs form beta(2)m(-) mice is inhibited by addition of soluble Fas-Ig fusion proteins or by pretreatment of the CTLs with the protein synthesis inhibitor emetime. In addition, LCMV-infected cell lines that are resistant to anti-Fas-induced apoptosis are refractory to lysis by these virus-specific CD4(+) CTLs. These data indicate that LCMV-specific CD4(+) CTLs from beta(2)m(-) mice use a Fas-dependent lytic mechanism. Intracranial (i.c.) infection of beta(2)m(-) mice with LCMV results in loss of body weight. Fas-deficient beta(2)m(-).lpr mice develop a similar wasting disease following i.c. infection. This suggests that Fas-dependent cytotoxicity is not required for LCMV-induced weight loss. A potential mediator of this chronic wasting disease is tumor necrosis factor (TNF)-alpha, which is produced by LCMV-specific CD4(+) CTLs. In contrast to LCMV-induced weight loss, lethal LCM disease in beta(2)m(-) mice is dependent on Fas-mediated cytotoxicity. Transfer of immune splenocytes from LCMV-infected beta(2)m(-) mice into irradiated infected beta(2)m(-) mice results in death of recipient animals. In contrast, transfer of these splenocytes into irradiated infected beta(2)m(-).lpr mice does not cause death. Thus a role for CD4(+) T-cell-mediated cytotoxicity in virus-induced immunopathology has now been demonstrated.

    AB - beta(2)-Microglobulin-deficient (beta(2)m(-)) mice generate a CD4(+) major histocompatibility complex class II-restricted cytotoxic (CTL) response following infection with lymphocytic choriomeningitis (LCM) virus (LCMV). We have determined the cytotoxic mechanism used by these CD4(+) CTLs and have examined the role of this cytotoxic activity in pathogenesis of LCM disease in beta(2)m(-) mice. Lysis of LCMV-infected target cells by CTLs form beta(2)m(-) mice is inhibited by addition of soluble Fas-Ig fusion proteins or by pretreatment of the CTLs with the protein synthesis inhibitor emetime. In addition, LCMV-infected cell lines that are resistant to anti-Fas-induced apoptosis are refractory to lysis by these virus-specific CD4(+) CTLs. These data indicate that LCMV-specific CD4(+) CTLs from beta(2)m(-) mice use a Fas-dependent lytic mechanism. Intracranial (i.c.) infection of beta(2)m(-) mice with LCMV results in loss of body weight. Fas-deficient beta(2)m(-).lpr mice develop a similar wasting disease following i.c. infection. This suggests that Fas-dependent cytotoxicity is not required for LCMV-induced weight loss. A potential mediator of this chronic wasting disease is tumor necrosis factor (TNF)-alpha, which is produced by LCMV-specific CD4(+) CTLs. In contrast to LCMV-induced weight loss, lethal LCM disease in beta(2)m(-) mice is dependent on Fas-mediated cytotoxicity. Transfer of immune splenocytes from LCMV-infected beta(2)m(-) mice into irradiated infected beta(2)m(-) mice results in death of recipient animals. In contrast, transfer of these splenocytes into irradiated infected beta(2)m(-).lpr mice does not cause death. Thus a role for CD4(+) T-cell-mediated cytotoxicity in virus-induced immunopathology has now been demonstrated.

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    T2 - Proceedings of the National Academy of Sciences

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