title: Sex steroids induce apoptosis of CD8+CD4+ double-positive thymocytes via TNF-alpha.
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-alpha. Anti-TNF-alpha monoclonal antibodies abrogated testosterone-induced DP apoptosis, and TNF-alpha-/- DP thymocytes were largely resistant to testosterone-mediated apoptosis in vivo. Testosterone accomplished this effect by upregulating TNF-alpha production and by simultaneously sensitizing DP thymocytes to TNF-alpha. Thus, TNF-alpha 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.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Guevara Patiño
authors.forename: M W
authors.initials: MW
authors.lastname: Marino
authors.forename: V N
authors.initials: VN
authors.lastname: Ivanov
authors.forename: J
authors.initials: J
authors.lastname: Nikolich-Zugich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015704:CD4 Antigens / Q000032:analysis*; D016827:CD8 Antigens / Q000032:analysis*; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000502:physiology; D013739:Testosterone / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D014409:Tumor Necrosis Factor-alpha; D013739:Testosterone