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Thymocyte-targeted overexpression of xiap transgene disrupts T lymphoid apoptosis and maturation
1Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.
Abstract:
The X-linked inhibitor of apoptosis (XIAP) and other members of the inhibitor of apoptosis (IAP) family can suppress apoptosis induced by a diverse variety of triggers. Functional studies done to date have focused on tissue culture models and adenovirus overexpression of XIAP and other IAP proteins. Here we report the phenotype of an engineered transgenic mouse overexpressing a human IAP, as well as assessing the long-term consequence of IAP overexpression. We document the relative protein expression levels of the endogenous mouse homologue to XIAP, mouse inhibitor of apoptosis (MIAP 3), within thymocyte and T cell subpopulations. The consequence of lymphoid-targeted overexpression of XIAP in transgenic mice suggests a physiological role for the endogenous protein, MIAP3. Xiap-transgenic mice accumulated thymocytes and/or T cells in primary and secondary lymphoid tissue, T cell maturation was perturbed, and transgenic thymocytes resisted a variety of apoptotic triggers both in vitro and in vivo. These observations imply a possible key function for the intrinsic cellular inhibitor XIAP in maintaining the homeostasis of the immune system.
Insights
Engineered mice overexpressing the X-linked inhibitor of apoptosis (XIAP) showed altered immune cell populations and resistance to cell death. This suggests XIAP plays a key role in maintaining immune system homeostasis.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The X-linked inhibitor of apoptosis (XIAP) protein family inhibits programmed cell death (apoptosis).
- Previous studies on XIAP function primarily used cell culture models and viral overexpression systems.
Purpose of the Study:
- To investigate the in vivo effects of XIAP overexpression using a transgenic mouse model.
- To assess the long-term consequences of XIAP overexpression on the immune system.
- To determine the expression levels of the mouse XIAP homologue, MIAP3, in immune cells.
Main Methods:
- Generation of transgenic mice overexpressing human XIAP.
- Analysis of thymocyte and T cell populations in lymphoid tissues.
- Assessment of thymocyte apoptosis resistance in vitro and in vivo.
- Quantification of endogenous MIAP3 protein expression.
Main Results:
- Transgenic mice exhibited accumulation of thymocytes and T cells.
- T cell maturation was disrupted in Xiap-transgenic mice.
- Overexpressed XIAP conferred resistance to various apoptotic stimuli.
- MIAP3 expression was documented in thymocyte and T cell subsets.
Conclusions:
- Lymphoid-targeted XIAP overexpression in mice suggests a critical physiological role for endogenous MIAP3.
- XIAP appears to be a key intrinsic cellular inhibitor involved in immune system homeostasis.
- These findings highlight XIAP's importance in regulating immune cell populations and survival.