Genetics of Apoptosis

induced cleavage of XIAP at Asp^24 generates a COOH-terminal fragment that
potentiates CD95-induced apoptosis (Deveraux et al., 1999).
These observations suggest that caspase-induced proteolysis of these survival
proteins may serve to amplify rapidly the caspase cascade, thereby potentiating death
receptor-induced apoptosis.

5.

Role of death receptor-induced apoptosis in the immune system

5. 1

Regulation of the immune response

Apoptosis plays an essential role in the immune system. The molecular regulation of
cell survival is a fundamental determinant of lymphocyte maturation, receptor
repertoire selection, homeostasis, and the cellular response to stressful stimuli, such
as DNA damage (Krammer, 2000). Increased apoptosis is involved in the
pathogenesis of diverse immune disorders. Conversely, genetic aberrations that render
cells incapable of executing their suicide program result in autoimmune disorders and
tumorigenesis. The physiologic role played by death receptors in the immune response
is summarized below.

Activation of immune and inflammatory responses

TNF-α is produced by activated T cells and macrophages. TNF-α or TNFR
knockout 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-α in immune and inflammatory responses,
TNF-α can also induce apoptosis in certain cell types or contexts. The molecular
mechanisms that underlie these divergent effects of TNF-α have been described
earlier.

Maintenance of lymphocyte homeostasis

The elimination of lymphocytes during development, receptor repertoire selection,
and the decay phase of the immune response involve death receptor-ligand
interactions.
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-

DEATH RECEPTORS IN APOPTOSIS 21