Two overlapping subdominant epitopes identified by DNA immunization induceprotective CD8(+) T-cell populations with differing cytolytic activities

Subdominant CDS' T-cell responses contribute to control of several viral in fections and to vaccine-induced immunity. Here, using the lymphocytic chori omeningitis virus model, we demonstrate that subdominant epitopes can be mo re reliably identified by DNA immunization than by other methods, permittin g the identification, in the virus nucleoprotein, of two overlapping subdom inant epitopes: one presented by L-d and the other presented by Kd. This su bdominant sequence confers immunity as effective as that induced by the dom inant epitope, against which > 90% of the antiviral CD8(+) T cells are norm ally directed. We compare the kinetics of the dominant and subdominant resp onses after vaccination with those following subsequent viral infection. Th e dominant CD8(+) response expands more rapidly than the subdominant respon ses, but after virus infection is cleared, mice which had been immunized wi th the "dominant" vaccine have a pool of memory T cells focused almost enti rely upon the dominant epitope. In contrast, after virus infection, mice wh ich had been immunized with the "subdominant" vaccine retain both dominant and subdominant memory cells. During the acute phase of the immune response , the acquisition of cytokine responsiveness by subdominant CD8(+) T cells precedes their development of lytic activity. Furthermore, in both dominant and subdominant populations, lytic activity declines more rapidly than cyt okine responsiveness. Thus, the lysis(low)-cytokine(competent) phenotype as sociated with most memory CD8(+) T cells appears to develop soon after anti gen clearance. Finally, lytic activity differs among CD8(+) T-cell populati ons with different epitope specificities, suggesting that vaccines can be d esigned to selectively induce CD8(+) T cells with distinct functional attri butes.