Nuclear Receptors and Thymocyte Apoptosis: Shaping the Immune Repertoire
Programmed cell death (PCD) plays a critical role in the generation of the antigen-specific immune repertoire. Both the T cell receptor (TCR) ligand-binding chains and immunoglobulin are generated randomly from the rearrangement of independent gene segments. While this process ensures the diversity of the immune cell receptor repertoire, it also results in the generation of T cells that express receptors that recognize self antigens in the context of self major histocompatibility complex (MHC)-encoded molecules with high affinity. The most effective way to deal with these potentially autoreactive cells is to eliminate them, a process referred to as “negative selection”. Deletion of potentially autoreactive T cells usually occurs in the thymus. Use of anti-TCR antibodies or bacterial superantigens (which mimic receptor occupancy by a natural ligand) during fetal thymic organ cultures results in PCD of immature CD4+ CD8+ thymocytes1,2, as does exposure of thymocytes from TCR-transgenic mice to the appropriate antigen3,4. The dying thymocytes manifest the classic apoptotic phenotype: membrane blebbing, cytoplasmic condensation, and chromatin clumping, accompanied by endonuclease-mediated cleavage of internucleosomal DNA1. Injection of cyclosporin A, which blocks activation-induced T cell hybridoma and thymocyte apoptosis5,6, prevents the deletion of a population of autoreactive T cells when the thymus regenerates after sublethal irradiation7,8.
KeywordsRetinoic Acid Negative Selection Thymic Epithelial Cell Thymocyte Apoptosis Steroid Receptor Expression
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