Sex shapes CD64 expression and vaccine-induced monocytic responses

Sex-specific differences influence vaccine-induced immunity, with females generally mounting more robust immune responses than males. While enhanced antibody production in females is well established, the cellular mechanisms underlying these differences remain elusive. Monocytes and monocyte-derived dendritic cells contribute to vaccine-induced immunity by capturing antibody-antigen immune complexes via Fc gamma receptors (FcγRs), positioning them as potential mediators of sex-biased vaccine responses. Here, we investigated sex-specific differences in FcγRI (CD64)-expressing monocytic cells in humans and mice. Using flow cytometry, we demonstrate that healthy women display higher frequencies of CD64-positive monocytes and elevated CD64 expression in peripheral blood compared with men. In mice, a similar sex-specific pattern was consistently reproduced across diverse experimental settings, including in vitro and in vivo conditions. Functional in vitro assays revealed that classical monocytes from female mice mediated stronger classical antigen presentation to CD4⁺ T cells than male-derived monocytes in a CD64-dependent manner, as reflected by increased IFNγ production. In parallel, female-derived monocytes also displayed enhanced cross-presentation to CD8⁺ T cells; however, this effect occurred independently of CD64. Following intramuscular vaccination, flow cytometric analysis demonstrated that female mice exhibited increased frequencies of CD64-positive monocytes at the injection site, accompanied by higher CD64 surface expression levels on these cells. In addition, females showed significantly greater accumulation of monocytic cells in dorsal lymph nodes compared with males. Notably, castration of male mice enhanced monocytic recruitment to muscle tissue following immunization, indicating a role for sex hormones in regulating monocytic responses to vaccination. Together, these findings identify sex-specific regulation of CD64⁺ monocytic cells as a mechanism associated with enhanced antigen presentation in females and suggest that this pathway contributes to stronger vaccine-induced immune responses. In this context, our data underscore the relevance of biological sex in shaping Fcγ receptor-mediated immune mechanisms relevant to vaccination.