Life-course immunology: reframing sex differences in the immune system to better understand women's health

Sex differences are observed in the immune system in innate and adaptive immune responses. These sex differences can be pronounced during periods of significant hormonal change for women, such as puberty, pregnancy, and menopause. Despite evidence of these immunological sex differences shifting and changing during the life course, some research imprecisely conceptualizes sex differences as simply comparative. The dynamic nature of sex differences in the immune system requires moving beyond static male-female comparisons that ignore life-stage transitions and instead adopting a life-course lens that recognizes how immune function-particularly in women-is continuously reshaped across biological transitions. Evidence demonstrates meaningful sex differences across immune-mediated conditions, infection outcomes, and reactogenicity, yet critical gaps remain in the understanding of mechanism and life-course variation in these immune responses. To meaningfully advance research on sex differences in immunity, studies must explicitly and intentionally account for life-stage transitions, moving beyond static male-female comparisons that do not account for life-stage transitions. This shift requires the use of research designs that appropriately consider sex differences and life stage and that studies are powered for life-stage immune questions. Sex differences in immunity are continuously reshaped by and across the lifespan due to aging, hormonal changes, and social and environmental exposures. The field of immunology and immunology research must reconsider life stage as a core principle of sex differences. Failure to intentionally study sex differences across the life course in immunology leaves major gaps in our understanding of immune function in women across the life course and drive disparities, inefficiencies, and inaccuracies in research, treatment, and clinical care.