CD4 Co-Receptor Regulates Sex-Specific NK Cell Responses to Acute Toxoplasma gondii Infection

Immunity to Toxoplasma gondii ( T. gondii ) is sexually dimorphic in humans and mice, with females having higher morbidity and mortality during immune dysfunction and HIV-AIDS. The mechanisms underlying these sex differences are unclear. We investigated how a lack of CD4+ T cells (CD4 co-receptor KO) impacted T. gondii survival in mice. Female CD4 co-receptor KO mice succumbed to T. gondii much faster than males. To dissect why female CD4 co-receptor KO mice died faster, we tested their NK cell responses to acute T. gondii infection compared to males. Although in wild-type (WT) animals, both sexes had similar increases in total NK cells and IFNγ + NK cells, infected CD4 co-receptor KO female mice had 50% fewer IFNγ+ NK cells than infected WT female mice. Infected male CD4 co-receptor KO had a similar increase in IFNγ+ NK cells as WT male mice. Since CD4 co-receptor deficient mice still have functional helper T cells that are CD4-, we next tested survival and NK cell responses in female and male MHCII deficient (MHCIIKO) animals, which completely lack helper CD4+T cells. Surprisingly, survival, NK cell numbers, and IFNγ+ NK cells were not significantly different between WT or MHCIIKO female and male mice. These results suggest CD4 co-receptor expression is required for survival via optimal NK cell responses during acute T. gondii infection only in female mice and not in male mice. Our findings reveal an unappreciated sexual dimorphic role of CD4 co-receptor expression in regulating NK cell responses to acute T. gondii infection.