Modulation of the CD8+ T cell response to subdominant epitopes of respiratory syncytial virus by deletion of an immunodominant epitope (43.9)

Abstract

Abstract Cytotoxic T lymphocytes (CTLs) are critical for control of respiratory syncytial virus (RSV) infection in humans and mice. Recently, we identified a new H-2Kd- restricted subdominant epitope in the RSV M2 protein. This finding allowed us to study the frequency of T lymphocytes responding two H-2Kd-restricted epitopes, M282–90 and M2127–135, following RSV infection in both lymphoid and non-lymphoid tissues. The ratio of T lymphocytes during the peak CTL response to RSV infection that were specific for immunodominant or subdominant was approximately 3:1 in the spleen and 10:1 in the lung. This ratio was observed consistently in primary or secondary infection. In addition, we showed that the kinetics of response against the two epitopes was regulated differently; the response to the subdominant epitope was delayed compared to the dominant epitope. In further studies, we demonstrated that modification of residues at positions 2 and 9 in the dominant M282–90 epitope altered the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 or mutant M2 proteins. Immunogenicity of the subdominant epitope M2127–135 was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to subdominant epitopes. Taken together, our findings have implications for understanding the immune response to RSV infection or vaccination and provide insight into methods for the rational design of vaccines that induce CD8+ T cells.