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

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Zajac, AJ, Quinn, Daniel, Cohen, PL and Frelinger, JA (1996) Fas-dependent CD4(+) cytotoxic T-cell-mediated pathogenesis during virus infection. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 93 (25). pp. 14730-14735. [Journal article]

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DOI: 10.1073/pnas.93.25.14730

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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
ID Code:22901
Deposited By:Dr Daniel Quinn
Deposited On:31 Jul 2012 10:28
Last Modified:31 Jul 2012 10:28

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