Sex steroids induce apoptosis of CD8(+)CD4(+) double-positive thymocytes via TNF-alpha

T cell production by the thymus, thymic size, cellularity and output all de crease drastically after puberty. Among the candidates that may mediate thi s decrease are the sex steroids: hypersecretion or pharmacological administ ration of these hormones has long been known to induce thymic hypocellulari ty, and their depletion yields thymic hypercellularity. Here we show that a typical sex steroid, testosterone, specifically targets CD8(+)CD4(+) doubl e-positive (DP) thymocytes for apoptosis via TNF-alpha. Anti-TNF-alpha mono clonal antibodies abrogated testosterone-induced DP apoptosis, and TNF-alph a(-/-) DP thymocytes were largely resistant to testosterone-mediated apopto sis in vivo. Testosterone accomplished this effect by upregulating TNF-alph a production and by simultaneously sensitizing DP thymocytes to TNF-alpha. Thus, TNF-alpha is the critical mediator of sex steroid-induced apoptosis i n thymocytes, and its manipulation should provide a point of intervention t o modulate T cell production in sex hormone disorders.