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Sex steroids induce apoptosis of CD8+CD4+ double-positive thymocytes via TNF-alpha
J A Guevara Patiño1, M W Marino, V N Ivanov
1Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
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.
Insights
Testosterone triggers thymus cell death by increasing TNF-alpha, a key mediator. This finding offers new ways to manage T cell production issues related to sex hormone imbalances.
Area of Science:
- Immunology
- Endocrinology
Background:
- Thymic T cell production declines post-puberty, potentially due to sex steroids.
- Sex steroids are known to influence thymic cellularity, with excess causing reduction and depletion causing increase.
Purpose of the Study:
- To investigate the role of testosterone in thymocyte apoptosis.
- To elucidate the mechanism by which testosterone affects thymic cellularity, specifically focusing on T cell development.
Main Methods:
- Investigated the effect of testosterone on CD8+CD4+ double-positive (DP) thymocytes.
- Utilized anti-TNF-alpha monoclonal antibodies and TNF-alpha knockout (TNF-alpha-/-) models in vivo.
- Assessed testosterone's impact on TNF-alpha production and DP thymocyte sensitivity to TNF-alpha.
Main Results:
- Testosterone specifically induces apoptosis in DP thymocytes through TNF-alpha.
- Anti-TNF-alpha antibodies blocked testosterone-induced DP apoptosis.
- DP thymocytes from TNF-alpha-/- mice showed resistance to testosterone-mediated apoptosis.
Conclusions:
- TNF-alpha is the critical mediator of testosterone-induced thymocyte apoptosis.
- Targeting TNF-alpha presents a potential therapeutic strategy for modulating T cell production in sex hormone-related disorders.