The impact of sex on the immune system explored at the single-cell level

Sex has a key role in disease susceptibility (in particular, autoimmunity). Sex differences in the immune system originate from genes and their interactions with both intrinsic and extrinsic factors. However, the cellular-level factors influencing sexual dimorphism are not fully understood. We thus examined immune sex differences at single-cell resolution to dissect the genetic impacts. Female-biased sex-differentially expressed genes (sex-DEGs) in multiple immune cells were involved in tumor necrosis factor alpha (TNF-α) signaling, whereas male DEGs were enriched for ribosomal-related functions. While cis-expression trait quantitative loci (eQTLs) were less common on sex chromosomes, we identified over 1,000 sex-specific eQTLs and 51 sex-interacting eQTLs on autosomes. When we examined the effect of genetic control on sex-DEGs, we found genetic variants affecting the female-biased expression of FCGR3A in natural killer (NK) cells (rs2099684) and ITGB2 in monocytes (rs760462), both of which are associated with systemic lupus erythematosus. Our work reveals biases masked in bulk analyses and highlights sexually dimorphic genes and pathways at baseline.