Molecular and cellular basis of the retrovirus resistance in I/LnJ mice.
Previously, we showed that IFN-gamma elicited by mouse mammary tumor virus (MMTV) infection in I/LnJ mice stimulated production of virus-neutralizing Abs, mostly of the IgG2a isotype. These Abs coated virions secreted by infected I/LnJ cells, and thus completely prevented virus transmission to offspring. However, the mechanism of virus neutralization by isotype-specific Abs remained unknown. Ab coating is capable of blocking virus infection by interfering with receptor-virus binding, by virus opsonization, by complement activation, and via FcgammaR-mediated effector mechanisms. The aim of the studies described in this work was to uncover the cellular basis of anti-virus Ab production, to evaluate the importance of the IgG2a subclass of IgGs in virus neutralization, and to investigate which of the blocking mechanisms plays a role in virus neutralization. We showed that I/LnJ-derived bone marrow cells, specifically IFN-gamma-producing CD4+ T cells, were key cells conferring resistance to MMTV infection in susceptible mice upon transfer. We also established that a unique bias in the subclass selection toward the IgG2a isotype in infected I/LnJ mice was not due to their potent neutralizing ability, as anti-virus Abs of other isotypes were also able to neutralize the virus, but were a product of virally induced IFN-gamma. Finally, we demonstrated that F(ab')2 of anti-MMTV IgGs neutralized the virus as efficiently as total IgGs, suggesting that Ab-mediated interference with viral entry is the sole factor inhibiting virus replication in I/LnJ mice. We propose and discuss possible mechanisms by which infected I/LnJ mice eradicate retrovirus.
Case
Laure K
LK
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Purdy
Alexandra
A
Golovkina
Tatyana V
TV
D019264:Adoptive Transfer; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008324:Mammary Tumor Virus, Mouse / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D014412:Tumor Virus Infections / Q000276:immunology; D014771:Virion / Q000276:immunology*
D000914:Antibodies, Viral; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007371:Interferon-gamma