IL-12 and IL-23 dependent NK cell response is essential for protective immunity against secondary Toxoplasma gondii infection

Abstract

Abstract Natural Killer (NK) cells can develop memory-like features and contribute to long term-immunity in mice and humans in response to viral infections. NK cells are critical for protecting against acute T. gondii infection. How they impact long-term immunity in response to the parasite and mechanism(s) involved is unknown. Using a vaccine-challenge model of parasite infection we addressed these questions. After lethal reinfection of vaccinated mice with or without NK cells, we find they are required for immune control of secondary parasite infection. Unexpectedly, secondary responses of CD4 and CD8 T cells are also reduced in the absence of NK cells during reinfection of vaccinated mice. NK cells mount a secondary response noted by increased IFNγ production, however, adoptive transfer and NK cell fate mapping reveal that T. gondii-experienced cells are not intrinsically different from naïve cells in persistence and ability to protect. This suggests a cell extrinsic mechanism controls protective NK cell response during secondary infection. Although NK cell IFNg is IL-12 dependent during acute T. gondii infection, using anti-IL-12p70 antibody or IL-12p35−/− mice we find that secondary NK cell response is not fully dependent upon IL-12. IL-23 depletion with anti-IL-23p19 in vivo also significantly reduces the secondary NK cell response suggesting both IL-12 and IL-23 are involved. Anti-IL-12p40 treatment, which blocks both IL-12 and IL-23, completely eliminates protective secondary NK cell response, supporting this hypothesis. These results identify a previously unknown protective role of NK cells during secondary T. gondii infection that is not only IL-12 dependent, but also requires IL-23 and may involve an interaction with T cells.