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Homeostasis of multicellular organisms is controlled not only by the proliferation and differentiation of cells but also by cell death (1). The death of cells during embryogenesis, metamorphosis, endocrine-dependent tissue atrophy, and normal tissue turnover is called programmed cell death. Most of programmed cell death proceeds by apoptosis, a process that includes condensation and segmentation of nuclei, condensation and fragmentation of the cytoplasm, and often extensive fragmentation of chromosomal DNA into nucleosome units.
Apoptosis in vertebrate development often occurs by default when cells fail to receive the extracellular survival signals needed to suppress an intrinsic cell suicide program (2); the survival factors can be produced by neighboring cells of a different type (a paracrine mechanism), or of the same type (an autocrine mechanism). In contrast, in the immune system there are situations where cells actively kill other cells; for example, cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells induce apoptosis in their targets such as virus-infected cells or tumor cells (3). In these cases, an effector molecule expressed at the surface of CTLs or NK cells or a soluble cytokine produced by these effector cells is thought to be responsible for target cell death.
Molecular and cellular characterization of Fas, a cell surface protein recognized by cytotoxic monoclonal antibodies, revealed its role as a receptor for a Fas ligand (FasL) (4). When FasL binds to Fas, the target cell undergoes apoptosis. Spontaneous mutations for Fas and FasL have been identified in mice, and from the phenotypes of these mutants and from studies on mechanisms of cytotoxicity, it was concluded that the Fas-FasL system is involved not only in CTL-mediated cytotoxicity but also is down-regulation of immune responses. In this article, we summarize current knowledge on Fas and FasL and discuss their physiological and pathological roles in the immune system.
Fas and Fas Ligand
In 1989 two groups independently isolated mouse-derived antibodies that were cytolytic for various human cell lines (5, 6). The cell surface proteins recognized by the antibodies were designated Fas and APO-1, respectively. The antibody to Fas (anti-Fas) was an immunoglobulin M (IgM) antibody, whereas the antibody to APO-1 was classified as IgG3. The Fas complementary DNA (cDNA) was isolated by expression cloning from a cDNA library of human KT-3 lymphoma cells...