Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination

Abstract

Females have generally more robust immune responses thanmales for reasons that are not well-understood. Here we useda systems analysis to investigate these differences by analyzingthe neutralizing antibody response to a trivalent inactivatedseasonal influenza vaccine (TIV) and a large number of immunesystem components, including serum cytokines and chemokines,blood cell subset frequencies, genome-wide gene expression, andcellular responses to diverse in vitro stimuli, in 53 females and 34males of different ages. We found elevated antibody responses toTIV and expression of inflammatory cytokines in the serum offemales compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3proteins in monocytes but not with the serological response to thevaccine. In contrast, using a machine learning approach, weidentified a cluster of genes involved in lipid biosynthesis andpreviously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, menwith elevated serum testosterone levels and associated genesignatures exhibited the lowest antibody responses to TIV. Theseresults demonstrate a strong association between androgens andgenes involved in lipid metabolism, suggesting that these could beimportant drivers of the differences in immune responses betweenmales and females.