SEXUAL-DIMORPHISM IN HUMAN IMMUNE SYSTEM AGING

Abstract

Abstract Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22–93 years of age using ATAC-seq, RNA-seq and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cells and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell-specific loci. Interestingly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. In a separate cohort (n=39) we studied how older adults respond to two available pneumococcal vaccines: T-dependent Prevnar and T-independent Pneumovax. How older adults respond to these vaccines at the molecular and cellular level, and whether there are pre-vaccination predictors for vaccine responsiveness, is poorly understood. To address this, we characterized serum antibody responses and peripheral blood leukocyte composition using flow cytometry and transcriptional profiles using RNA-seq, in healthy older adults before and after vaccination. The vaccines induced comparable serological responses and increases in the number of ICOS+ T follicular helper cells. A shared plasmablast transcriptional signature (IGHG2, IGHA1, IGHA2) was induced by both vaccines ten days after vaccination, which is distinct from influenza vaccine responses. Importantly, the pre-vaccination (baseline) ratio of Th1/Th17 cells predicted responsiveness to Prevnar but not to Pneumovax. Interestingly, women had higher levels of Th1/Th17; and responded stronger to Prevnar compared to men. This study uncovered how older adults respond to different pneumococcal vaccines and demonstrated the significance of considering biological sex and the immune cell composition for precision vaccinology.