Ligation of the antigen-specific B-cell receptor (BCR) alone is an insufficient signal
to activate a B cell and instead results in apoptosis or functional elimination.
Activation of a B cell to effector function requires delivery of a second signal by
activated helper T cells. Activation of the CD4+ T cell (by engagement of the TCR
and ligation of CD28) induces expression by the T cell of a 39-kDa glycoprotein
called gp39 or CD40 ligand (CD40L), whose receptor, CD40, is present on B cells
(Foy et al., 1994; Renshaw et al., 1994; Xu et al., 1994; Foy et al., 1996). In addition
to CD40-CD40L, two other receptor-ligand pairs within the TNF-R/TNF
superfamilies regulate B-cell survival. Ligation of the B-cell receptors, TACI and
BCMA, by BLyS (TALL-1, THANK, BAFF, zTNF4) and APRIL, respectively,
promotes B-cell survival, proliferation, and immunoglobulin production (Mackay et
al., 1999; Moore et al., 1999; Mukhopadhyay et al., 1999; Khare et al., 2000; Yan et
al., 2000). There are striking similarities between the BLyS-TACI and CD40L-CD40
systems; both ligands are TNF family members expressed on activated T cells and
DCs, and both receptors are TNFR homologs expressed on B cells. Upon engagement
by their respective ligands, both TACI and CD40 induce activation of NF-κB- and
NF-κB-dependent expression of survival proteins (Bcl-xL) that rescue B cells from
BCR- or CD95-induced apoptosis (Lagresle et al., 1996). In the absence of such
protection, cell death may be triggered via CD95-CD95L interactions as well as
CD95-independent BCR-induced signals that lead to mitochondrial disruption and
caspase activation (Berard et al., 1999; Craxton et al., 1999).
After clonal expansion, antigen-reactive lymphocytes are titrated down until the
lymphoid cell pool is restored to its basal level. The decay of the immune response is
achieved by elimination of lymphocytes via instructive apoptosis involving death
receptor/ligand systems. While CD40 engagement is required for B-cell proliferation,
it also promotes the expression of CD95 on activated B cells. Activated APCs and T
cells synthesize the adversarial death ligands that kill B cells at the end of an immune
response (Scott et al., 1996).
Induction of cell death by cytotoxic T cells and NK cellsMature CD8+ T cells (cytotoxic T lymphocytes [CTLs]) and natural killer (NK) cells
are effectors of innate and adaptive immune responses to intracellular pathogens,
cancer cells, or transplanted tissues. CTLs and NK cells induce apoptosis of these
targets by two major mechanisms. One mechanism involves ligation of CD95 on
target cells by FasL expressed on CTLs (Li, J.H. et al., 1998). The second mechanism
involves calcium-dependent exocytosis of the CTL-derived granule proteins, perforin
and granzymes (Heusel et al., 1994; Shresta et al., 1995). Perforin facilitates the
delivery of granzyme B into target cells via an as yet obscure mechanism that does
not require plasma membrane pore formation (Shi et al., 1997; Metkar et al., 2002).
Granzyme B, the prototypic member of this family of serine proteases, induces
cleavage and activation of multiple caspases, including caspase3, -6, -7, -8, -9, and
-10 (MacDonald et al., 1999). Granzyme B also cleaves BID at a site distinct from
that targeted by caspase-8 (Alimonti et al., 2001). Akin to tBID (generated by
DEATH RECEPTORS IN APOPTOSIS 23