chapter  1
-Death receptors in apoptosis 19
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Activation of immune and inflammatory responses TNF-ос is produced by activated T cells and macrophages. TNF-a or TNFR knock­ out mice exhibit a deficient inflammatory response to bacterial endotoxin and have an exaggerated susceptibility to microbial infections (Smith et al, 1994). While these findings demonstrate a role of TNF-a in immune and inflammatory responses, TNF-a can also induce apoptosis in certain cell types or contexts. The molecular mechanisms that underlie these divergent effects of TNF-a have been described earlier. Maintenance o f lymphocyte homeostasis The elimination of lymphocytes during development, receptor repertoire selection, and the decay phase of the immune response involve death receptor-ligand inter­ actions. Deletion of thymocytes and peripheral T cells. Pre-T cells undergo maturation and rearrangement of T-cell antigen receptor (TCR) genes in the thymus. T cells that fail to undergo TCR rearrangement are incapable of stimulation by self major his­ tocompatibility (MHC) antigen-peptide complexes and suffer death by neglect. Since this process is impaired in transgenic mice carrying a dominant-negative form of the adapter FADD, death receptors may be involved in the induction of apoptosis at this pre-TCR stage of development (Newton et al., 2000). Thymocytes that survive pre-TCR selection mature into CD4+CD8+ T cells and undergo further positive and negative selection depending on the affinity of their TCRs for self MHC antigens. T cells with high affinity for self MHC molecules and peptide are eliminated, and the surviving mature CD4+ MHC class-II-restricted and CD8+ MHC class-I-restricted T cells leave the thymus and enter the peripheral T-cell pool in secondary lymphoid organs. The negative and positive selection that occurs dur­ ing T-cell development is instrumental for self-MHC restriction and prevention of autoimmunity. Studies of T-cell receptor transgenic mice indicate that CD95 is involved with peripheral, but not thymic, deletion of T cells (Singer and Abbas, 1994; Van Pārijs et al., 1996). Although the TCR repertoire is not altered in mice that have genetic deficiencies of the CD95-CD95L system (Ipr and gld mice), CD95-induced apoptosis may be involved in the negative selection of thymocytes that encounter high antigen concentrations (Kishimoto et al., 1998; Newton et al., 1998). The role of other death receptor-ligand interactions (such as DR4/DR5Apo2L/TRAIL) in thymic deletion is as yet unknown.