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

Abstract

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 (CD62Llow CD44hi) 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.