Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis

TLDR

Sex and aging shape the human immune system, yet their precise effects remain incompletely understood. Overall, this work expands our knowledge of sex differences in the immune system in humans. The study found that females have fewer NK cells but more plasma cells and heightened BAFF/APRIL signaling, indicating a stronger adaptive immune response, whereas males exhibit higher NK cell percentages and elevated pro‑inflammatory gene expression, with aging further increasing monocytes, reducing naïve T cells, and amplifying sex‑specific gene differences.

Abstract

Sex and aging influence the human immune system, resulting in disparate responses to infection, autoimmunity, and cancer. However, the impact of sex and aging on the immune system is not yet fully elucidated. Using small conditional RNA sequencing, we found that females had a lower percentage of natural killer (NK) cells and a higher percentage of plasma cells in peripheral blood compared with males. Bioinformatics revealed that young females exhibited an overrepresentation of pathways that relate to T and B cell activation. Moreover, cell-cell communication analysis revealed evidence of increased activity of the BAFF/APRIL systems in females. Notably, aging increased the percentage of monocytes and reduced the percentage of naïve T cells in the blood and the number of differentially expressed genes between the sexes. Aged males expressed higher levels of inflammatory genes. Collectively, the results suggest that females have more plasma cells in the circulation and a stronger BAFF/APRIL system, which is consistent with a stronger adaptive immune response. In contrast, males have a higher percentage of NK cells in blood and a higher expression of certain proinflammatory genes. Overall, this work expands our knowledge of sex differences in the immune system in humans.