CD4 co-receptor regulates sexual dimorphic NK cell responses to T. gondiiinfection.

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Abstract Immunity to Toxoplasma gondiiis 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. Since CD4+ T cells are very low during HIV/AIDS and females are more susceptible to Toxoplasmic encephalitis (TE) when they have AIDS, we investigated how a lack of CD4 co-receptor expression (CD4KO) and CD4+ T cells (MHCIIKO) impacted T. gondiisurvival and innate immune responses in mice. Female CD4KO mice succumbed to T. gondiimuch faster than male CD4KO mice. To dissect why female CD4KO mice died faster we tested their NK cell responses to acute T. gondiiinfection compared to male CD4KO mice. Although in wild type (WT) animals both sexes had similar increases in NK cell numbers and IFNg production, infected CD4KO female mice had 50% fewer IFNg+ NK cells than infected WT female mice. However, infected male CD4KO had the same number of NK cells producing IFNg compared to 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 have very few helper CD4+T cells. To our surprise survival, NK cell numbers, and IFNg+ NK cells were not significantly different between WT or MHCIIKO female and male mice. These results suggest only in female mice and not in male mice, CD4 co-receptor expression is required for survival via optimal NK cell responses during acute T. gondiiinfection. Our findings reveal an unappreciated sexual dimorphic role of CD4 co-receptor expression in regulation of NK cell responses to acute T. gondiiinfection. National Institute of General Medical Sciences (P20GM103432)