TAP-1 indirectly regulates CD4⁺ T cell priming in Toxoplasma gondii infection by controlling NK cell IFN-γ production

To investigate if transporter associated with antigen processing (TAP)–1 is required for CD8⁺ T cell–mediated control of Toxoplasma gondii in vivo, we compared the resistance of TAP-1^−/−, CD8^−/−, and wild-type (WT) mice to infection with the parasite. Unexpectedly, TAP-1^−/− mice displayed greater susceptibility than CD8^−/−, β₂-microglobulin^−/− (β₂m^−/−), or WT mice to infection with an avirulent parasite strain. The decreased resistance of the TAP-1^−/− mice correlated with a reduction in the frequency of activated (CD62L^low CD44^hi) and interferon (IFN)-γ–producing CD4⁺ T cells. Interestingly, infected TAP-1^−/− mice also showed reduced numbers of IFN-γ–producing natural killer (NK) cells relative to WT, CD8^−/−, or β₂m^−/− mice, and after NK cell depletion both CD8^−/− and WT mice succumbed to infection with the same kinetics as TAP-1^−/− animals and displayed impaired CD4⁺ T cell IFN-γ responses. Moreover, adoptive transfer of NK cells obtained from IFN-γ^+/+, but not IFN-γ^−/−, animals restored the CD4⁺ T cell response of infected TAP-1^−/− mice to normal levels. These results reveal a role for TAP-1 in the induction of IFN-γ–producing NK cells and demonstrate that NK cell licensing can influence host resistance to infection through its effect on cytokine production in addition to its role in cytotoxicity.