chapter  22
Genetics of Apoptosis
Pages 5

Activated APCs and T cells synthesize the adversarial death ligands that kill В cells at the end of an immune response (Scott et a ly 1996). Induction o f cell death by cytotoxic T cells and NK cells Mature 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 apopto­ sis 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 a l , 1998). The second mechanism involves calcium-dependent exocytosis of the CTL-derived granule proteins, perforin and granzymes (Heusel etai, 1994; Shresta etai, 1995). Perforin facilitates the delivery of granzyme В into target cells via an as yet obscure mecha­ nism that does not require plasma membrane pore formation (Shi et a l , 1997; Metkar et a l , 2002). Granzyme В, 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 eta ly 1999). Granzyme В also cleaves BID at a site distinct from that targeted by caspase-8 (Alimonti et a l , 2001). Akin to tBID (generated by caspase-8), the truncated BID generated by granzyme В (gtBID) translocates to the mitochondrial membrane and promotes the release of mito­ chondrial death factors via BAX or BAK (Heibein et a ly 2000; Alimonti et a ly 2001; Wang, N.S. et a ly 2001). Since granzyme В and CD95L can both activate the BIDBAX/BAK death-signaling pathway, they provide independent mechanisms of inducing target cell apoptosis. Accordingly, cells deficient in CD95 or overexpress­ ing c-FLIP remain susceptible to CTL-induced death (Kataoka et a ly 1998). It will be important to determine whether interruption of a distal step of the death-sig­ naling pathway shared by CD95L and granzyme В (such as loss of BAX/BAK) reduces CTL-induced death of type II target cells that require cross-talk between the extrinsic and intrinsic pathways to undergo apoptosis. Such genetic impedi­ ments to CTL-induced death may be an important mechanism by which tumor cells evade immune surveillance. Establishment o f zones o f immune privilege Immune-privileged sites such as the eye, brain, and the testes may evade damage by constitutively expressing CD95L to counterattack and eliminate CD95-expressing infiltrating lymphocytes (Green and Ferguson, 2001). Some reports suggest that expression of CD95L by certain types of cancer cells may protect such tumors from immune surveillance. While ectopic expression of FasL by gene transfer can confer immune privilege on some tissues, it can also induce a granulocytic infiltrate and increased rejection in tissue transplants. The role of CD95L-CD95 interactions in the creation of zones of immune privilege in tumors or tissue allografts in vivo remains debatable (Green and Ferguson, 2001).