Thymic involution occurs independently of stromal Fas signaling during aging and pregnancy

Age-related involution of the thymus is a hallmark of immunosenescence, characterized by a progressive decline in the supply of T cells. Restoration of thymic function has therefore been proposed as a potential strategy to prevent age-associated diseases, including infections, autoimmune disorders and immunodeficiency. However, the cellular and molecular mechanisms underlying thymic involution remain incompletely understood. It has been suggested that Fas, a death receptor expressed in thymic stromal cells, is involved in age-related thymic involution. While Fas is well known for its role in activation-induced cell death in peripheral immune cells, its function in thymic stromal compartments remains unclear. To determine the role of stromal Fas, we generated thymic epithelial cell (TEC)- and fibroblast (Fb)-specific Fas conditional knockout mice and examined thymic phenotypes under steady-state, pregnancy-induced, and aging conditions. Fas and Fas ligand (FasL) expression in thymic cell populations were analyzed by flow cytometry and quantitative PCR. Fas was predominantly expressed in medullary TECs and medullary fibroblasts, whereas FasL was highly expressed in thymic CD4⁺ NKT cells. Unexpectedly, deletion of Fas in TECs or Fbs did not affect thymic homeostasis under steady-state conditions and failed to rescue either age-related or pregnancy-induced thymic involution. Furthermore, systemic Fas-deficient mice also exhibited age-related thymic atrophy. These findings demonstrate that Fas signaling in thymic stromal cells is not essential for both age-related and pregnancy-induced thymic involution. Taken together, our findings redefine the role of Fas in the thymus and suggest that mechanisms other than stromal Fas signaling govern thymic involution during aging and pregnancy.