Responses against a subdominant CD8⁺ T cell epitope protect against immunopathology caused by a dominant epitope

CD8⁺ T cell responses are critical for the control of virus infections. Following infection, epitope-specific responses establish an unpredictable but reproducible pattern of dominance that is dictated by a large number of both positive and negative factors. Immunodomination, or diminution of subdominant epitope-specific responses by dominant epitopes, can play a substantial role in the establishment of epitope hierarchy. To determine the role of a dominant (K^dM2_82-90) and a subdominant (D ^bM_187-195) epitope of respiratory syncytial virus in viral control and immunodomination, MHC-binding anchor residues in the two epitopes were mutated individually in recombinant infectious viruses, greatly reducing or deleting the epitope-specific CD8⁺ T cell responses. Neither mutation negatively affected viral clearance in mice, and compensation by the unmutated epitope was seen in both cases, whereas compensation by five other subdominant epitopes was minimal. Mutation of the dominant K^dM2 _82-90 response resulted in effective viral clearance by the subdominant epitope with less illness, whereas mutation of the subdominant D^bM_187-195 response resulted in overcompensation of the already dominant K^dM2_82-90 epitope, and increased severity of illness. Increased illness was associated with poor functionality of the abundant population of CD8⁺ T cells specific to the dominant K ^dM2_82-90 epitope, as measured by the percentage and magnitude of IFN-γ production. These data demonstrate efficient viral clearance, and a protective effect of subdominant CD8⁺ T cell responses.