Vaccination with TAT-Antigen Fusion Protein Induces Protective, CD8+ T Cell-Mediated Immunity Against Leishmania Major

In murine leishmaniasis, healing is mediated by IFN-γ-producing CD4+ and CD8+ T cells. Thus, an efficacious vaccine should induce Th1 and Tc1 cells. Dendritic cells (DCs) pulsed with exogenous proteins primarily induce strong CD4-dependent immunity; induction of CD8 responses has proven to be difficult. We evaluated the immunogenicity of fusion proteins comprising the protein transduction domain of HIV-1 TAT and the Leishmania antigen LACK (Leishmania homolog of receptors for activated C kinase), as TAT-fusion proteins facilitate major histocompatibility complex class I-dependent antigen presentation. In vitro, TAT–LACK-pulsed DCs induced stronger proliferation of Leishmania-specific CD8+ T cells compared with DCs incubated with LACK alone. Vaccination with TAT–LACK-pulsed DCs or fusion proteins plus adjuvant in vivo significantly improved disease outcome in Leishmania major-infected mice and was superior to vaccination with DCs treated with LACK alone. Vaccination with DC+TAT–LACK resulted in stronger proliferation of CD8+ T cells when compared with immunization with DC+LACK. Upon depletion of CD4+ or CD8+ T cells, TAT–LACK-mediated protection was lost. TAT–LACK-pulsed IL-12p40-deficient DCs did not promote protection in vivo. In summary, these data show that TAT-fusion proteins are superior in activating Leishmania-specific Tc1 cells when compared with antigen alone and suggest that IL-12-dependent preferential induction of antigen-specific CD8+ cells promotes significant protection against this important human pathogen.