IL-12p40-independent induction of protective immunity upon multiple Plasmodium berghei irradiated sporozoite immunizations.

Both IFN-gamma and IL-12 play critical roles in defence against malaria. In a previous study, using Plasmodium yoelii model, C57BL/6 IFN-gamma receptor deficient mice (IFN-gammaR-/-) failed to develop protective immunity after a single immunization with irradiated sporozoites, but were protected after multiple immunizations. In contrast, in another study, BALB/c IFN-gamma gene knockout mice (IFN-gamma-/-) and BALB/c IL-12-deficient mice (IL-12p40-/- and IL-12p35-/-) were unable to mount protective immune response even after multiple immunizations with the same irradiated parasites. To better define the role of IFN-gamma and IL-12p40 in sterile protection, we selected the C57BL/6 model. Wild-type and IL-12p40-/- mice were immunized with a single or multiple doses of P. berghei irradiated sporozoites. While the wild-type mice were able to rapidly produce IFN-gamma and mount a protective immune response after a single immunization with irradiated sporozoites, IL-12p40-/- mice were neither able to produce IFN-gamma nor were protected. However, both strains of mice were able to produce IFN-gamma and were protected after three doses of irradiated sporozoites. Protection was partially and largely mediated by CD4+ T cells and CD8+ T cells, respectively. Thus, IL-12p40 plays an important role in mediating early protection by irradiated sporozoite immunization but is dispensable for protective immunity induced by several immunizations with irradiated sporozoites. Moreover, treatment of hyperimmune IL-12p40-/- mice with rhIL-18 bp-Fc, an inhibitor of IL-18 activity, did not abrogate protection indicating that IL-18 is not required for the effector phase of the immune response; it remains possible, however, that IL-18 may compensate for the lack of IL-12p40 in the induction phase of the immune response.