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(−/−), β(2)-microglobulin(−/−) (β(2)m(−/−)), 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 β(2)m(−/−) 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.