title: The level of friend retrovirus replication determines the cytolytic pathway of CD8+ T-cell-mediated pathogen control.
abstract: Cytotoxic T cells (CTL) play a central role in the control of viral infections. Their antiviral activity can be mediated by at least two cytotoxic pathways, namely, the granule exocytosis pathway, involving perforin and granzymes, and the Fas-FasL pathway. However, the viral factor(s) that influences the selection of one or the other pathway for pathogen control is elusive. Here we investigate the role of viral replication levels in the induction and activation of CTL, including their effector potential, during acute Friend murine leukemia virus (F-MuLV) infection. F-MuLV inoculation results in a low-level infection of adult C57BL/6 mice that is enhanced about 500-fold upon coinfection with the spleen focus-forming virus (SFFV). Both the low- and high-level F-MuLV infections generated CD8+ effector T cells that were essential for the control of viral replication. However, the low-level infection induced CD8+ T cells expressing solely FasL but not the cytotoxic molecules granzymes A and B, whereas the high-level infection resulted in induction of CD8+ effector T cells secreting molecules of the granule exocytosis pathway. By using knockout mouse strains deficient in one or the other cytotoxic pathway, we found that low-level viral replication was controlled by CTL that expressed FasL but control of high-level viral replication required perforin and granzymes. Additional studies, in which F-MuLV replication was enhanced experimentally in the absence of SFFV coinfection, supported the notion that only the replication level of F-MuLV was the critical factor that determined the differential expression of cytotoxic molecules by CD8+ T cells and the pathway of CTL cytotoxicity.
authors.affiliation: Institut für Virologie, des Universitätsklinikums Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Zelinskyy
authors.forename: Sandra
authors.initials: S
authors.lastname: Balkow
authors.forename: Simone
authors.initials: S
authors.lastname: Schimmer
authors.forename: Tanja
authors.initials: T
authors.lastname: Werner
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D005089:Exocytosis; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005622:Friend murine leukemia virus / Q000235:genetics*; D053804:Granzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology; D014779:Virus Replication
chemical_list: D053222:Fas Ligand Protein; D053804:Granzymes