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

AJ Zajac, Daniel Quinn, PL Cohen, JA Frelinger

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    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.
    Original languageEnglish
    Pages (from-to)14730-14735
    JournalPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Volume93
    Issue number25
    DOIs
    Publication statusPublished - Dec 1996

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