Silencing an immunodominant epitope of hepatitis B surface antigen reveals an alternative repertoire of CD8 T cell epitopes of this viral antigen

Immunodominance hierarchies operating in immune responses to viral antigens limit the diversity of the elicited T cell responses. The L^d/S_28–39-restricted CD8 T cell response to the hepatitis B surface antigen (HBsAg or S) prevents copriming of D^d- and K^b-restricted CD8 T cell responses. We exchanged L to V at position S₃₉ of HBsAg to construct mutant S_L39V. Comparable levels of wild-type S and mutant S_L39V were produced by transiently transfected cells, and mice immunized with the pCI/S and pCI/S_L39V DNA vaccines showed comparable serum antibody responses to HBsAg. The pCI/S but not pCI/S_L39V DNA vaccination induced L^d/S_28–39-specific CD8 T cell responses. However, the pCI/S_L39V DNA vaccine efficiently primed CD8 T cell responses to the subdominant D^d- and K^b-restricted epitopes, confirming the immunosuppressive phenotype of the L^d/S_28–39-specific CD8 T cell response. A single point mutation within the HBsAg can hence completely silence a ‘dominant’ CD8 T cell response thereby facilitating priming of a multispecific repertoire of suppressed, ‘subdominant’ epitopes. The data have practical implications for understanding HBV-specific CD8 T cell responses and for the design of novel vaccination strategies.