Major Histocompatibility Complex Class II-Restricted, CD4+ T Cell-Dependent and -Independent Mechanisms Are Required for Vaccine-Induced Protective Immunity against Coxiella burnetii

To understand the role of major histocompatibility complex class I (MHC-1) and MHC-II in vaccine-mediated protection against Coxiella burnetii, we evaluated the protective efficacy of a formalin-inactivated C. burnetii Nine Mile phase I vaccine (PIV) in beta(2)-microglobulin-deficient (B2m KO) and MHC-II-deficient (MHC-II KO) mice. Vaccination reduced disease severity in wild-type (WT) and B2m KO mice but failed to reduce bacterial burden in MHC-II KO mice. This suggests that the MHC-II antigen presentation pathway is required for PIV-mediated protection against C. burnetii infection. MHC-I and MHC-II affect antibody isotype switching, since both PIV-vaccinated B2m KO and MHC-Il KO mice produced less Coxiella-specific IgG than PIV-vaccinated WT mice. Interestingly, MHC-II and CD4 deficiencies were not equivalent in terms of splenomegaly and bacterial clearance. This demonstrates a partial role for CD4(+) T cells while revealing MHC-II-restricted, CD4-independent mechanisms. Adoptive transfer of CD4(+)T cells from PIV-vaccinated WT mice to naive CD4-deficient (CD4 KO) mice demonstrated that antigen-experienced CD4(+) T cells are sufficient to generate protection. Conversely, transfer of naive CD4(+ )T cells to PIV-vaccinated CD4 KO mice exacerbates disease. Using Tbet-deficient (Tbet KO) mice, we showed a partial role for Th1 subset CD4(+) T cells in vaccine protection. Furthermore, Th1-independent roles for Tbet were suggested by significant differences in disease between PIV-vaccinated Tbet KO and CD4 KO mice. Interferon gamma was shown to contribute to the host inflammatory response but not bacterial clearance. Collectively, these findings suggest that vaccine-induced protective immunity against a murine model of experimental Q fever requires MHC-II-restricted, CD4(+) T cell-dependent and -independent mechanisms that can be exploited for a new-generation human Q fever vaccine.