CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Cell, Vol. 100, 129±138, January 7, 2000, Copyright 2000 by Cell Press Immunology: Improving on Nature Review in the Twenty-First Century Abul K. Abbas* and Charles A. Janeway Jr.² notion at the time, one that challenged existing concepts *Department of Pathology of how proteins conformed to the shapes of other inter- University of California San Francisco School acting proteins. Nevertheless, the clonal selection the- of Medicine ory became the foundation for our understanding of the San Francisco, California 94123 specificity and development of immune responses. The ² Section of Immunobiology molecular understanding of how the diverse repertoire Yale University School of Medicine of antigen receptors is generated came with the studies New Haven, Connecticut 06520 of Susumu Tonegawa in the 1970s (Tonegawa et al., 1977). Based on this work, and its many subsequent refinements, it is now known that the antigen receptors Introduction of B and T lymphocytes are encoded by genes that are Immunology is the study of the body's defenses against produced by somatic recombination of gene segments infection. The birth of immunology as an experimental during maturation of the cells. The recombination pro- science dates to Edward Jenner's successful vaccina- cess is initiated by the RAG proteins, and presence of tion against smallpox in 1796 (Jenner, 1798). The world- RAG genes during phylogeny identifies the evolutionary wide acceptance of vaccination led to mankind's great- time of appearance of the adaptive immune system, est achievements in preventing disease, and smallpox which is just past the appearance of vertebrates (Agra- is the first and only human disease that has been eradi- wal et al., 1998; Hiom et al., 1998). The jawless fish lack cated. During the twentieth century, the impact of immu- RAG genes and lymphoid organs, while cartilaginous nology has moved beyond defense against infections. fish have RAG genes and a quite well-developed adap- Our growing understanding of the immune system has tive immune system. Recombination of antigen receptor influenced a variety of different biomedical disciplines gene segments serves three critical functions: it allows and has played an important role in the study and treat- a vast number of receptors to be generated from a small ment of many human diseases (Abbas et al., 1997; Jane- number of genes, it maximizes the diversity of the recep- way et al., 1999; Paul, 1999). However, it is still clear tors by introducing sequence variations at the sites of that the primary role of the immune system is resistance recombination, and it regulates the development of indi- to infection. In this review we survey the evolution of vidual lymphocytes, which is tightly linked to the status immunology as a scientific discipline and speculate on of gene rearrangement. Somatic recombination of anti- some of the directions in which the field is likely to move gen receptor genes is the paradigm for studying gene in the future. Among these, we hope that it will become rearrangement during cell maturation. possible to use manipulation of the adaptive immune Immunological Memory response to overcome many human diseases. These Immunological memory refers to the ability of the im- are currently treated only with drugs that do not exploit mune system to respond more strongly to successive the specificity of adaptive immunity. We also point out exposures to the same antigen. The classical definition some of the areas in which studying the immune system of memory came from the realization that infection with a has led to the discovery of principles with broad implica- particular microbe or vaccination rendered an individual tions for diverse biological processes. resistant to subsequent exposures to that microbe; that is, they were immune to the specific pathogen. Much The Basis for Specificity and Memory in Adaptive effort has been devoted to defining the phenotypic and Immune Responses functional characteristics of memory cells, and much The earliest studies of protective immunity against infec- has been learned about what these cells do. However, tions established the two defining characteristics of fundamental questions about the signals that are re- adaptive immunity, namely, specificity for the antigenic quired to generate memory cells, and the mechanisms determinants of pathogens, and the memory of having responsible for the survival of these cells in the apparent been exposed to the same pathogen previously, called absence of antigen, remain unsolved. This uncertainty immunological memory. Implicit in the phenomenon of is mainly a reflection of the fact that immunological specificity is the concept of the enormous diversity of memory has to be studied in vivo, and only recently the receptor repertoires of lymphocytes. have methods been developed to identify numerically Specificity and Diversity rare antigen-specific populations in the midst of large The specificity of immune responses was initially in- numbers of lymphocytes with diverse specificities (Alt- ferred from studies of protective immunity and vaccina- man et al., 1996; Murali-Krishna et al., 1998; Ogg et al., tion against microbes, which was by definition pathogen 1998). specific. These early studies culminated in the formula- tion of the clonal selection hypothesis in the 1950s, The Initiation of Immune Responses: which proposed that clones of immunocompetent cells What Lymphocytes See with unique receptors exist prior to exposure to anti- The key breakthrough that opened the way for our mod- gens, and only cells with specific receptors are selected ern understanding of the immune system was the identi- by antigen for subsequent activation (Figure 1) (Burnet, fication by Jim Gowans of small lymphocytes as the 1959). The idea that specificity for diverse antigens ex- cellular units of clonal selection in adaptive immunity ists prior to encounter with these antigens was a radical (Gowans et al., 1962). We now know that there are two Cell 130 Figure 1. The Clonal Selection Theory of Lymphocytes Schematic of clonal selection hypothesis il- lustrating the idea that each naõÈve lympho- cyte has a different receptor specificity, each of which can bind a different antigenic deter- minant. When a pathogen is recognized by the cells, in this case by two different anti- genic determinants, then the cells that bind to these determinants are selected to proliferate or undergo clonal expansion, and then differ- entiate into effector cells that either secrete antibody or mediate various effector mecha- nisms of cell-mediated immunity. classes of antigen-specific lymphocytes with receptors bound to one of that individual's 5±15 MHC allelic prod- for antigens, B and T cells, which function as the media- ucts (Babbitt et al., 1985). As there are over 100 alleles tors of humoral immunity and cell-mediated immunity, at several loci within the MHC, this means that the MHC respectively. The use of monoclonal antibodies (Kohler is the most polymorphic set of loci within the human and Milstein, 1975) to identify different populations of genome. lymphocytes and to isolate these populations for func- The dual specificity of T cells, for peptide antigens tional and biochemical analyses has been instrumental and for MHC molecules, led to many theories about how in understanding lymphocyte biology. In fact, the ease T cells recognized antigens. The great controversy was of producing fairly homogeneous populations of lym- whether T cells expressed a single receptor that saw phocytes with defined specificitiesÐby purification, cell both peptide and MHC, or one receptor for each. Early cloning, and transgenic technologyÐis the principal studies showed that fusing two distinct T cell lines did reason why lymphocytes have taught us a great deal not generate four different specificities, as predicted by about fundamental biological phenomena. the dual specificity model, but rather the two original One of the most impressive accomplishments of im- specificities of the parent clones, as would be predicted munology is the elucidation of antigen recognition by from the single receptor hypothesis (Kappler et al., lymphocytes. We now know that B cell antigen receptors 1981). Biochemical analyses of the T cell antigen recep- bind a wide variety of macromolecules and small chemi- tor also showed a single receptor molecule, but the cals in different conformations. However, the greatest identification of the T cell receptor (TCR) for antigen surprises have come from studies of T cell antigen rec- came from molecular cloning (Hedrick et al., 1984). The ognition. This story began with the discovery, in the definitive results that established the structural basis of 1960s and 1970s, that different inbred strains of animals MHC restriction came with the solution of the crystal did or did not respond to simple polypeptide antigens, structure of MHC molecules, which showed that these and this immune responsiveness mapped to a highly molecules contained bound peptides (Bjorkman et al., polymorphic genetic locus that had been discovered as 1987) (Figure 2), and ultimately in the solution of the the target of graft rejection and was therefore called crystal structures of T cell receptors binding to MHC: the major histocompatibility complex (MHC) (Benacerraf peptide complexes (Figure 2) (Garboczi et al., 1996; Gar- and McDevitt, 1972). These phenomena eluded explana- cia et al., 1996). These