The activation, localization, phenotypic changes, and function of CFSE-labeled naive influenza-specific CD8(+) and CD4(+) T cells following influenza infection were examined. Response of adoptively transferred CD8(+) T cells was seen earliest in draining lymph node. Highly activated cells were found later in the lung, airways, and spleen, were cytolytic, and expressed IFN-gamma upon restimulation. Similar amounts of division at early time points, but higher numbers of CD8(+) T cells, were detected at 9 and 30 days postinfection after cotransfer of CD4(+) and CD8(+) T cells followed by infection. Transfer of much smaller numbers of CD4(+) and CD8(+) T cells led to more extensive expansion but the same difference in final number between the two cell types. These studies demonstrate how CD8(+) and CD4(+) T cells respond to influenza at early time points postinfection and the differential kinetics of antigen-specific CD4(+) and CD8(+) T cells.