[摘要]：Activated lymphocytes and lymphoid-tissue inducer cells express lymphotoxins (LTs), which are essential for the organogenesis and maintenance of lymphoreticular microenvironments. Here we describe that T-cell-restricted overexpression of LT induces fulminant thymic involution. This phenotype was prevented by ablation of the LT receptors tumor necrosis factor receptor (TNFR) 1 or LT beta receptor (LT beta R), representing two non redundant pathways. Multiple lines of transgenic Lt alpha beta and Lt alpha mice show such a phenotype, which was not observed on overexpression of LT beta alone. Reciprocal bone marrow transfers between LT-overexpressing; and receptor-ablated mice show that involution was not due to a T cell-autonomous defect but was triggered by TNFR1 and LT beta R signaling to radioresistant stromal cells. Thymic involution was partialty prevented by the removal of one allele of LT beta R but not of TNFR1, establishing a hierarchy in these signaling events. infection with the lymphocytic choriomeningitis virus triggered a similar thymic pathology in wit, but not in Tnfr1(-/-) mice. These mice displayed elevated TNF alpha in both thymus and plasma, as well as increased Us on both CD8(+) and CD4(-)CD8(-) thymocytes. These findings suggest that enhanced T cell-derived LT expression helps to control the physiological size of the thymic stroma and accelerates its involution via TNFR1/LT beta R signaling in pathological conditions and possibly also in normal aging.
