CD4⁺ T cells are required during priming but not the effector phase of antibody-mediated IFN-γ-dependent protective immunity against pulmonary Francisella novicida infection

We have previously demonstrated the protective efficacy of intranasal vaccination with a defined Francisella tularensis subsp. novicida ΔiglC mutant (KKF24) against pulmonary F. novicida U112 challenge. In this study, we further characterized the mechanisms of KKF24-induced immunity. Intranasally vaccinated KKF24 C57BL/6 major histocompatibility class (MHC) class II ^-/- mice produced minimal antigen-specific interferon (IFN)-γ and serum antibodies and were highly susceptible (0% survival) to F. novicida challenge, compared to MHC class I^-/- or wild-type mice (both 100% survival). Protective immunity could be transferred by immune serum into recipient wild type, but not IFN-γ^-/- mice. The protective effect of KKF24 vaccination against the respiratory F. novicida U112 challenge was not abrogated by anti-CD4 neutralizing antibody treatment and was not conferred by adoptive transfer of KKF24-specific CD4⁺ T cells. The protective effect of antibody was partially dependent upon Fc receptor-mediated clearance. Taken together, our data indicate that CD4⁺ T cells are required for priming, but not during the effector phase, of anti-KKF24 antibody-mediated IFN-γ-dependent immunity against pulmonary F. novicida infection.