Identification and characterization of immunodominance hierarchies within vaccine-relevant CD8 T cell responses

Abstract

Immunodominance hierarchies operating in immune responses to viral antigens limit the diversity of the elicited CD8 T cell responses. I evaluated in I-Ab+/A2-HHD-II and HLA-DR1+/A2-DR1 mice the HLA-A*0201-restricted, multispecific CD8 T cell responses to the human cytomegalovirus (HCMV) pp65 antigen. Vaccination of mice with pp65-encoding DNA elicited high IFNgamma+ CD8 T cell frequencies to the dominant e6 epitope and low responses to the subdominant e3 and e8 epitopes. Abrogation of the e6-specific immunity efficiently enhanced e3- and e8-specific T cell responses by a mutated DNA vaccine. The immunodominant e6-specific CD8 T cell response depends on CD4 T cell ‘help’. Injection of monospecific DNA- or peptide-based vaccines encoding the e3 or e8 epitope into HLA-A*0201 tg mice elicited CD8 T cells. Co-delivering the antigenic peptides with different heterologous CD4 T cell helper epitopes enhanced e6-specific CD8 T cell responses. CD4 T cell epitope(s) can thus provide efficient ‘help’ for establishing pp65-e6 immunodominance in vaccinated mice. In the second part of my thesis I analyzed CD8 T cell responses against the hepatitis B surface antigen (HBsAg). Two Kb-restricted epitopes, i.e. the Kb/S190 and the Kb/S208 epitope, have been mapped. These epitopes were thought to be generated by alternative antigen processing/presentation: (i) the Kb/S190-epitope in an ‘endogenous’ pathway; (ii) the Kb/S208-epitope in an ‘exogenous’ or cross-presentation pathway. I showed that inactivation of the Kb/S190-epitope in HBsAg-encoding DNA vaccines significantly improved Kb/S208-specific CD8 T cell responses. This identified a novel immunodominance hierarchy. Moreover, protein- and DNA-based vaccines elicited distinct Kb/S190- and Kb/208-specific immune responses in the tolerogenic milieu of HBV tg mice, expressing either endogenous or endo-/exogenous HBsAg in hepatocytes (HCs). These results have practical implications for the design of new T cell-stimulating vaccines.