Comprehensive profiling of phenotypic features of memory T- and B-cells from birth to the onset of old age

Abstract

Human aging is accompanied by profound and continuous remodeling of the immune system, characterized by rhythmic, stage-specific patterns. These features are characterized by waves of cellular differentiation, network reorganization, and functional recalibration, a phenomenon encompassed by the concept of immunobiography. This study focuses on T- and B-cell memory immunophenotypes that shape adaptive immunity, including interferon-activated cells from healthy volunteers of both sexes, aged 9 months to 65 years, stratified into 12 consecutive age subgroups. Significant shifts were concentrated in intermediate age subgroups, particularly at 5–6 years, 10–19 years (the most pronounced), and 20–29 years. Although women exhibited an earlier onset of changes, men demonstrated greater lifelong variability in differentiated subsets, especially for early effector CD4 + cells. Additionally, other cell subsets showed variability, especially in men, including early effector CD4 + and CD8 + , interferon- mediated CD4 + and CD8 + , central and effector memory CD4 + , non-interferon-mediated CD4 + , and naïve CD19 + B‐cells, predominantly between 10 and 39 years. Signature analyses confirmed sex-specific peaks occurring at distinct ages. Naïve cells displayed the highest overall connectivity, whereas B-cell network connectivity increased with age in women but decreased sharply in men after 20 years. Notably, the upregulation of immune memory cell subsets was accompanied by an increase in global connectivity. Our findings indicate that immune memory remodeling across the human lifespan occurs in discrete, sex-dependent waves, probably shaped by cumulative antigen exposure and endocrine transitions. These trajectories may differentially balance adaptive immunity and inflammatory differentiation, potentially influencing long-term immune resilience and susceptibility to chronic inflammatory conditions.