Fas-dependent CD4+ cytotoxic T-cell-mediated pathogenesis during virus infection.
beta 2-Microglobulin-deficient (beta 2m-) mice generate a CD4+ major histocompatibility complex class II-restricted cytotoxic T-lymphocyte (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 2m- mice. Lysis of LCMV-infected target cells by CTLs from beta 2m- mice is inhibited by addition of soluble Fas-Ig fusion proteins or by pretreatment of the CTLs with the protein synthesis inhibitor emetine. 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 2m- mice use a Fas-dependent lytic mechanism. Intracranial (i.c.) infection of beta 2m- mice with LCMV results in loss of body weight. Fas-deficient beta 2m- Jpr 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 2m- mice is dependent on Fas-mediated cytotoxicity. Transfer of immune splenocytes from LCMV-infected beta 2m- mice into irradiated infected beta 2m- mice results in death of recipient animals. In contrast, transfer of these splenocytes into irradiated infected beta 2m- Jpr mice does not cause death. Thus a role for CD4+ T-cell-mediated cytotoxicity in virus-induced immunopathology has now been demonstrated.
Zajac
A J
AJ
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599, USA.
Quinn
D G
DG
Cohen
P L
PL
Frelinger
J A
JA
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D001613:beta 2-Microglobulin / Q000172:deficiency; D019014:fas Receptor / Q000276:immunology*
D001613:beta 2-Microglobulin; D019014:fas Receptor