Through cognate interaction between antigen-specific B-cell and CD4+ αβ T cells, the CD4+ αβ T cells secrete cytokines that initiate immunoglobulin (Ig) class switching from IgM to IgG. In this study, we show that formalin-inactivated influenza PR8 virus induces virus-specific IgM and IgG responses in the absence of CD4+ T cells and that all four subclasses of IgG are produced. The immunized CD4-deficient mice were also found to be completely protected against lethal infection with live, pathogenic influenza virus. The ability of CD4+ T-cell-deficient mice to generate these IgG responses was not found to be impaired when these mice were depleted of CD8+ T cells with an anti-CD8 monoclonal antibody. In contrast, αβ T-cell- deficient mice (TCRβ[(-/-)]) were not found to produce significant amounts of IgG upon immunization with formalin-inactivated PR8 virus. These results suggest that CD4- CD8- double-negative αβ T cells are playing a role in regulating Ig class switching in the absence of CD4+ T cells.