Heterosubtypic Immunity to Influenza A Virus in Mice Lacking IgA, All Ig, NKT Cells, or γδ T Cells

Abstract

The mechanisms of broad cross-protection to influenza viruses of different subtypes, termed heterosubtypic immunity, remain incompletely understood. We used knockout mouse strains to examine the potential for heterosubtypic immunity in mice lacking IgA, all Ig and B cells, NKT cells (CD1 knockout mice), or γδ T cells. Mice were immunized with live influenza A virus and compared with controls immunized with unrelated influenza B virus. IgA−/− mice survived full respiratory tract challenge with heterosubtypic virus that was lethal to controls. IgA−/− mice also cleared virus from the nasopharynx and lungs following heterosubtypic challenge limited to the upper respiratory tract, where IgA has been shown to play an important role. Ig−/− mice controlled the replication of heterosubtypic challenge virus in the lungs. Acute depletion of CD4+ or CD8+ T cell subsets abrogated this clearance of virus, thus indicating that both CD4+ and CD8+ T cells are required for protection in the absence of Ig. These results in Ig−/− mice indicate that CD4+ T cells can function by mechanisms other than providing help to B cells for the generation of Abs. Like wild-type mice, CD1−/− mice and γδ−/− mice survived lethal heterosubtypic challenge. Acute depletion of CD4+ and CD8+ cells abrogated heterosubtypic protection in γδ−/− mice, but not B6 controls, suggesting a contribution of γδ T cells. Our results demonstrate that the Ab and cellular subsets deficient in these knockout mice are not required for heterosubtypic protection, but each may play a role in a multifaceted response that as a whole is more effective than any of its parts.

Protection against lethal influenza virus challenge by RNA interferencein vivo

“…TCID 50 assays were performed as described in ref. 30. Briefly, lung homogenates or tissue culture supernatants were assayed for virus infectivity on MDCK by endpoint dilution for cytopathic effect with a 10-fold dilution series.…”

DNA Vaccine Expressing Conserved Influenza Virus Proteins Protective Against H5N1 Challenge Infection in Mice

“…Enzyme-linked immunosorbent assay (ELISA) was performed as described previously (15) on plates coated with lysates of influenza virus–infected cells. Hemagglutination inhibition (HI) was performed by standard methods with sera pretreated with receptor-destroying enzyme (36).…”

“…Animal studies have demonstrated potent and long-lasting heterosubtypic immunity, that is, exposure to a virus of one subtype protects against challenge infection with another subtype (10–15). The mechanisms of heterosubtypic immunity are not completely understood but likely include both T-cell immunity, in particular CD8+ cytotoxic T-lymphocytes (CTL) (16,17) and CD4+ T cells (13), as well as antibodies to conserved epitopes (18).…”

Sympathetic nervous system control of anti-influenza CD8+T cell responses

“…Total IgG titers were determined by ELISA against lysates of PR8-infected MDCK cells as described previously (32).…”