Heterosubtypic immunity to influenza A virus in mice lacking IgA, all Ig, NKT cells, or gamma delta T cells

The mechanisms of broad cross-protection to influenza viruses of different subtypes, termed heterosubtypic immunity, remain incompletely understood. W e used knockout mouse strains to examine the potential for heterosubtypic i mmunity in mice lacking IgA, all Ig and B cells, NKT cells (CD1 knockout mi ce), or gamma delta T cells. Mice were immunized with live influenza A viru s and compared with controls immunized with unrelated influenza B virus. Ig A(-/-) mice survived full respiratory tract challenge with heterosubtypic v irus that was lethal to controls. IgA(-/-) mice also cleared virus from the nasopharynx and lungs following heterosubtypic challenge limited to the up per respiratory tract, where IgA has been shown to play an important role. Ig(-/-) mice controlled the replication of heterosubtypic challenge virus i n the lungs. Acute depletion of CD4(+) or CD8(+) T cell subsets abrogated t his 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 pr oviding help to B cells for the generation of Abs. Like wild-type mice, CD1 (-/-) mice and gamma delta (-/-) mice survived lethal heterosubtypic challe nge. Acute depletion of CD4(+) and CD8(+) cells abrogated heterosubtypic pr otection in gamma delta (-/-) mice, but not B6 controls, suggesting a contr ibution of gamma delta T cells. Our results demonstrate that the Ab and cel lular subsets deficient in these knockout mice are not required for heteros ubtypic protection, but each may play a role in a multifaceted response tha t as a whole is more effective than any of its parts.