A potent role for memory CD8⁺ T cells in heterologous immunity was shown with a respiratory mucosal model of viral infection. Memory CD8⁺ T cells generated after lymphocytic choriomeningitis virus (LCMV) infection were functionally activated in vivo to produce interferon-γ (IFN-γ) during acute infection with vaccinia virus (VV). Some of these antigen-specific memory cells selectively expanded in number, which resulted in modulation of the original LCMV-specific T cell repertoire. In addition, there was an organ-selective compartmental redistribution of these LCMV-specific T cells during VV infection. The presence of these LCMV-specific memory T cells correlated with enhanced VV clearance, decreased mortality and marked changes in lung immunopathology. Thus, the participation of pre-existing memory T cells specific to unrelated agents can alter the dynamics of mucosal immunity and disease course in response to a pathogen.