The IL-12- and IL-23-Dependent NK Cell Response Is Essential for Protective Immunity against Secondary Toxoplasma gondii Infection

NK cells can develop cell-intrinsic memory-like characteristics. Whether they develop these characteristics during Toxoplasma gondii infection is unknown. We addressed this question and dissected the mechanisms involved in secondary NK cell responses using a vaccine-challenge mouse model of T. gondii infection. NK cells were required for control of and survival after secondary T. gondii infection. NK cells increased in number at the reinfection site and produced IFN-γ. To test if these T. gondii experienced NK cells were intrinsically different from naive NK cells, we performed NK cell adoptive transfer into RAG2/cγ-chain^-/- mice, NK cell fate mapping, and RAG1^-/- mice vaccine-challenge experiments. Although NK cells contributed to immunity after reinfection, they did not develop cell-intrinsic memory-like characteristics after T. gondii vaccination. The mechanisms required for generating these secondary NK cell responses were investigated. Secondary NK cell responses were CD4⁺ or CD8⁺ T cell independent. Although IL-12 alone is required for NK cell IFN-γ production during primary T. gondii infection, in the absence of IL-12 using IL-12p35^-/- mice or anti-IL-12p70, secondary NK cell responses were only partially reduced after reinfection. IL-23 depletion with anti-IL-23p19 in vivo also significantly reduced the secondary NK cell response. IL-12 and IL-23 blockade with anti-IL-12p40 treatment completely eliminated secondary NK cell responses. Importantly, blockade of IL-12, IL-23, or both significantly reduced control of parasite reinfection and increased parasite burden. Our results define a previously unknown protective role for NK cells during secondary T. gondii infection that is dependent on IL-12 and IL-23.