MECHANISMS OF HETEROSUBTYPIC IMMUNITY TO LETHAL INFLUENZA-A VIRUS-INFECTION IN FULLY IMMUNOCOMPETENT, T-CELL-DEPLETED, BETA(2)-MICROGLOBULIN-DEFICIENT, AND J-CHAIN-DEFICIENT MICE

Immunity that is cross-protective between different influenza A virus subtypes (termed heterosubtypic immunity) can be demonstrated readily in some animals but only rarely in humans. Induction of heterosubtypic immunity in humans by vaccines would provide public health benefit, p erhaps offering some protection against pandemics or other new influen za A strains. Therefore, we studied mechanisms mediating heterosubtypi c immunity in mice. Immunization with either A/H1N1 or A/H3N2 virus pr otected mice against mortality following heterosubtypic challenge whil e providing modest reductions in lung virus titers. No cross-protectio n was seen with distantly related type B influenza virus. Depletion of CD4(+) or CD8(+) T cells or both around the time of challenge had no significant effect on survival, indicating that these cells are not re quired at the effector stage. beta(2)-microglobulin knockout mice coul d be protected readily against heterosubtypic challenge, confirming th at class I-restricted T cells are not required. In beta(2)-microglobul in -/- mice, depletion of CD4(+) T cells partially abrogated heterosub typic immunity, showing that they play a role in these mice. Passive t ransfer of Abs to naive recipients protected against subsequent challe nge with homologous but not heterosubtypic virus. Because a role for s ecretory Abs has been suggested, we studied dependence on the I chain, which is required for polymeric Ig receptor-mediated IgA transport. I chain knockout mice were readily protected by heterosubtypic immunity , indicating that polymeric Ig receptor-mediated transport is not requ ired. Better understanding of heterosubtypic immunity should be valuab le in analyzing new vaccines, including peptide and DNA vaccines, inte nded to induce broadly cross-reactive immunity.