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MARY COLLIN!; CELL DEATH Death by a thousand cuts The recent discovery of apoptotic cells in the thymus suggests tlhat apoptosis, the mechanism of programmed cell death in development, may be a more general regulatory mechanism. It was first demonstrated by Wyilie in 1980 that lymphoid cells, treated with glucocorticoids, enter a ‘suicide’ pro- gramme involving the rapid degradation of much of the cell chromatin to oligonucleosomes, followed by loss of plasma membrane integrity [l]. This programmed cell death, known as apoptosis, had previously been ob- served morphologically as a condensation of cytoplasm, clumping of chromatin and plasma membrane blebbing. Programmed cell death is common in animal develop- ment; it has been most fully analysed in the nematode Gzenorbabdit& ekgam, where mutations in two genes prevent almost all :such events [2]. Recent lindings sug- gest that the regulation of the vertebrate immune system also involves the cells being induced to tidy up their af fairs and depart when circumstances dictate. During development of the ‘ I’lymphocyte repertoire, au- toreactive cells capable of recognizing self-antigens pre- sented by self-major histocompatibility complex (MHC) molecules, must be eliminated. This deletion of a sub- set of deveIoping (cells occurs in the thymus. A logical mechanism would jinvolve induction of the death of such autoreactive cells on recognition of self-antigen. Because autoreactive Cells are only a small fraction of immature T cells, all studies of the mechanism of this step have used systems where bulk deletion is induced. Early ex- periments used an anti-CD3 antibody, which binds to all T cell antigen receptors, to demonstrate that triggering of T cells within the thymus does indeed lead to pro- grammed cell death, accompanied by the characteristic DNA degradation [ 3,4]. Induction of apoptosis can also be demonstrated in thymuses treated with a ‘superanti- gen’ , staphylococcal enterotoxin B, which is recognized by a significant fraction of T cell antigen receptors [5]. And, most recently, by using mice transgenic for a T cell antigen receptor recognizing a specific peptide, it was demonstrated that administration of the peptide resulted in thymic apoptosis, and loss of cells carrying the trans- genie receptor [6]. Thus, recognition of antigen by de- veloping T cells re;sults in the induction of programmed cell death (see Figure). Why immature T cells die, whereas mature T cells pro- liferate in responsle to antigen, remains a mystery. Per- haps the auxiliary molecules expressed by immature cells with their antigen receptors differ from those expressed by mature cells and transmit a ‘death’ signal [7]. Al- ternatively, the level of cytokines required to stimulate proliferation may not be achieved in the thymic microen- vironment. Why is apoptosis used as the mechanism of T cell death? The answer may be that, unlike apoptosis, necrosis of a large number of thymocytes would leave behind immunogenic debris such as DNA, resulting in an inflammatory response, damaging the thymus and itnpair- ing thymic selection. Macrophages have been shown to recognize and ingest apoptotic lymphocytes specifically [B], implying that dying cells express surface molecules signalling that they should be rapidly cleared. The positive selection of B lymphocytes to retain only those that produce high a&-&y antibodies to foreign anti- gens occurs in the germinal centres of lymph nodes. Here athnity maturation of the immune response occurs fol- lowing somatic mutation of immmunoglobulin variable region genes. In this case, selection is achieved by res- cue of those cells that receive a positive signal follow- ing antigen recognition by their surface immunoglobu- lin. Liu et a2. have demonstrated that this process may also involve apoptosis 191.They prepared B lymphocytes from germinal centres, and demonstrated that the cells entered apoptosis rapidly in culture unless their surface immunoglobulin receptors were stimulated with an anti- body. Therefore, in contrast to T lymphocyte selection, in this case the default pathway is death (see Figure). A similar, ‘death in the absence of signal’ , mechanism may operate to regulate the development from multipotential precursors in bone marrow of all cells of the haematopoi- etic system (see Figure). Williams et al. demonstrated that bone marrow progenitor cell lines, dependent on interleukin-3 for their growth in culture, undergo apop- tosis when interleukir-3 is removed [lo]. Erythropoietin also prevents apoptosis in activated erythroid progenitor cells [I 11. As removal of haematopoietic cells from the marrow microenvironment results in the death by ‘apop: tosis of most of the cells 1121, it seems that they are nor- mally maintained there, viable but not necessarily pro- liferating. Any stimulation of haematopoiesis by growth factors may then result in activated cells, programmed to die on factor removal. This would provide a mech- anism to limit the extent of regenerative haematopoiesis, which could also function in the regulation of normal haematopoiesis. This article has concentrated on cells of the haematopoi- etic system, but what about other cells? Cancer chemo- therapists have for some time used a diverse range of drugs that probably share one feature, the ability to in duce apoptosis. These include not only the glucocor- ticoids used in the treatment of lymphoid malignan ties, but also two categories of agents commonly used in the treatment of solid tumours. The first comprises @ 1991 Current Biology
