Ageing and female sex progressively remodel B‐ and T‐cell compartments to strain peripheral T‐cell tolerance to red blood cell autoantigens

Summary Warm autoimmune haemolytic anaemia (WAIHA) disproportionately affects older individuals and females, yet the mechanisms by which ageing and sex influence immune tolerance to red blood cell (RBC) autoantigens are incompletely understood. In preclinical models, tolerance to RBC antigens depends almost exclusively on peripheral CD4 + T‐cell regulation. Here, we used a murine model of primary autoimmune haemolytic anaemia to delineate age‐ and sex‐associated changes in immune cell subsets that precede tolerance failure. We show that ageing induces remodelling of B‐ and T‐cell compartments, including expansion of innate‐like B1 cells, accumulation of CD11c + T‐bet + age‐associated B cells (ABCs), and a shift towards pro‐inflammatory CD4 + T cells, including interferon gamma (IFN‐γ) producing T helper‐1 (TH1) and CD39‐expressing cells. Despite preserved regulatory pathways early in life, regulatory T‐cell frequencies declined with age. Notably, regulatory T cells from adult female mice exhibited reduced suppressive capacity during a timeframe that coincides with the emergence of autoantibody production. Functional studies revealed that the tolerogenic immune environment effectively restrains autoreactive T cells in young hosts, whereas ageing leads to a partial, sex‐biased degradation of this control. Together, these findings demonstrate that ageing and sex progressively challenge peripheral immune tolerance to RBC autoantigens, lowering the threshold for autoantibody‐mediated disease.