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 during 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 Parijs et al., 1996).
Although the TCR repertoire is not altered in mice that have genetic deficiencies of
the CD95-CD95L system (lpr 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/DR5-Apo2L/TRAIL) in thymic deletion
is as yet unknown.
Peripheral T cells are activated by cross-linkage of the TCR by the MHC-peptide
complex together with costimulatory signals delivered by engagement of the CD28
receptor on the T cell by members of the B7 family expressed on APCs. Costimulation
of T cells protects cells from TCR-induced apoptosis via activation of NF-κB- and
NF-κB-dependent expression of antiapoptotic proteins, such as Bcl-xL and c-FLIP
(Boise et al., 1995; Khoshnan et al., 2000). TCR ligation in the absence of
costimulatory signals result in T-cell apoptosis via mechanism(s) that do not require
CD95-CD95L interactions (Van Parijs et al., 1996). Following clonal expansion,
antigen-specific T cells acquire an apoptosis-sensitive phenotype that enables their
eventual demise during the decay phase of the immune response. This form of
instructive apoptosis (termed ‘activation-induced cell death’ [AICD]) is required to
return the expanded pool of cells to baseline levels. Unlike TCR-induced death of
resting T cells, AICD is mediated by CD95-CD95L interactions at its initiation
(Singer and Abbas, 1994; Alderson et al., 1995; Brunner et al., 1995; Dhein et al.,
1995; Ju et al., 1995) and the TNF-α-TNFR system at a later phase of execution
(Zheng et al., 1995). However, AICD may also involve other death receptors-ligands
(such as Apo2L/TRAIL) or death-inducing mechanism(s) that activate caspases and/
or disrupt mitochondria independent of death receptor-ligand interactions (Martinez-
Lorenzo et al., 1998; Hildeman et al., 1999; Spaner et al., 1999).
Instructive apoptosis of B cells. B cells express cell-membrane receptors (antibodies)
with single antigen specificity. The specificity of the immune response is achieved by
antigen binding and selection of pre-existing clones of antigen-specific lymphocytes.
Autoreactive B cells are deleted in the bone marrow. Mature B cells that populate
secondary lymphoid organs undergo somatic hypermutation with elimination of low-
affinity or autoreactive B-cell mutants (Lam and Rajewsky, 1998). Although B cells
do not express CD95L, they express CD95 and may be susceptible to elimination by
CD95L expressed by T cells and APCs (Scott et al., 1996). It is possible that such
fratricidal death receptor-ligand interactions may play a role in elimination of low-
affinity or autoreactive B cells.
22 GENETICS OF APOPTOSIS