Sex steroids induce apoptosis of CD8+CD4+ double-positive thymocytes via TNF-α

Abstract

T cell production by the thymus, thymic size, cellularity and output all decrease drastically after puberty. Among the candidates that may mediate this decrease are the sex steroids: hypersecretion or pharmacological administration of these hormones has long been known to induce thymic hypocellularity, and their depletion yields thymic hypercellularity. Here we show that a typical sex steroid, testosterone, specifically targets CD8+CD4+ double-positive (DP) thymocytes for apoptosis via TNF-α. Anti-TNF-α monoclonal antibodies abrogated testosterone-induced DP apoptosis, and TNF-α(-/-) DP thymocytes were largely resistant to testosterone-mediated apoptosis in vivo. Testosterone accomplished this effect by up-regulating TNF-α production and by simultaneously sensitizing DP thymocytes to TNF-α. Thus, TNF-α is the critical mediator of sex steroid-induced apoptosis in thymocytes, and its manipulation should provide a point of intervention to modulate T cell production in sex hormone disorders.