Heterosubtypic immunity to lethal influenza A virus infection is associated with virus-specific CD8(+) cytotoxic T lymphocyte responses induced in mucosa-associated tissues

Heterosubtypic immunity, defined as cross-reactive immune responses to infl uenza virus of a different serotype than the Virus initially encountered, w as investigated in association with virus-specific cytotoxic T lymphocyte ( CTL) responses induced in systemic and mucosa-associated lymph nodes after immunization via different routes. Mice immunized by the pulmonary route wi th live nonpathogenic influenza virus, strain Udorn (H3N2), survived challe nge with mouse-adapted pathogenic influenza virus, strain PR/8/34 (H1N1). T hese mice developed strong heterosubtypic CTL responses in spleen, cervical lymph nodes (CLN), and mediastinal lymph nodes (MLN). Alternately, only 20 % of mice immunized intravenously, intraperitoneally, or intranasally survi ved the challenge: all of these developed CTL responses in spleen and CLN, but not in MLN. Direct correlation between short-term and long-term memory heterosubtypic CTL responses induced in MLN and host recovery after lethal infection indicates that these CTL responses may play an important role in heterosubtypic immunity. Furthermore, induction and maintenance of memory C TL in regional mucosa-associated lymphoid tissues are highly dependent on m ucosal immunization. The results implicate the mechanism of heterosubtypic immunity and should be an important consideration in the development of pro tective mucosal vaccines against variant strains of influenza and HIV. (C) 1999 Academic Press.