Integrated analysis of sex differences in human dendritic cell, monocyte, and natural killer cell subsets

Sex-associated differences in the innate immune system fundamentally influence immune responses, yet subset-specific cellular heterogeneity is often overlooked in population-level studies. To characterize these differences at a granular level, we performed integrated immune profiling-using multiparameter flow cytometry, transcriptomics, and functional assays-on peripheral blood mononuclear cells from 91 healthy mainland Chinese donors. Our analysis revealed significant, conserved sexual dimorphism across major innate immune networks. In dendritic cells (DCs), females possessed a significantly higher frequency of plasmacytoid DCs (pDCs) exhibiting enhanced basal interferon-stimulated gene (ISG) expression and elevated IFN-β production upon stimulation, whereas males showed higher frequencies of Axl⁺ and CD1c⁺ DCs. Furthermore, males exhibited higher overall monocyte frequencies driven by classical monocytes, displaying heightened inflammatory signatures, elevated ICAM-1 protein expression, and the induction of stronger, Th17-skewed CD4⁺ T cell proliferation. Conversely, female monocytes were enriched for antigen presentation pathways, antiviral ISGs, and Th2 T cell polarization. Among natural killer (NK) cells, males demonstrated a higher proportion of mature CD56^dim subsets, while females had higher proportions of CD56^bright and CD56^neg subsets characterized by enhanced signaling, higher expression of activating receptors, and greater secretion of cytotoxic markers. Ultimately, these findings provide a comprehensive, subset-specific map of innate immune sexual dimorphism, demonstrating that female innate immune cells are fundamentally primed for enhanced antiviral interferon responses and robust NK effector functions, whereas male profiles are characterized by heightened inflammatory signatures and cellular maturation.