Immunology: Improving on Nature in the Twenty-First Century

Abstract

Immunology is the study of the body's defenses against infection. The birth of immunology as an experimental science dates to Edward Jenner's successful vaccination against smallpox in 1796 (Jenner, 1798). The worldwide acceptance of vaccination led to mankind's greatest achievements in preventing disease, and smallpox is the first and only human disease that has been eradicated. During the twentieth century, the impact of immunology has moved beyond defense against infections. Our growing understanding of the immune system has influenced a variety of different biomedical disciplines and has played an important role in the study and treatment of many human diseases (1Abbas A.K Lichtman A.H Pober J.S Cellular and Molecular Immunology. Third Edition. W.B. Saunders, Philadelphia1997Google Scholar, 26Janeway C.A Travers P Walport M Capra D Immunobiology. Fourth Edition. Garland Publishing, London1999Google Scholar, 49Paul W.E Fundamental Immunology. Lippincott-Raven, Philadelphia1999Google Scholar). However, it is still clear that the primary role of the immune system is resistance to infection. In this review we survey the evolution of immunology as a scientific discipline and speculate on some of the directions in which the field is likely to move in the future. Among these, we hope that it will become possible to use manipulation of the adaptive immune response to overcome many human diseases. These are currently treated only with drugs that do not exploit the specificity of adaptive immunity. We also point out some of the areas in which studying the immune system has led to the discovery of principles with broad implications for diverse biological processes. The earliest studies of protective immunity against infections established the two defining characteristics of adaptive immunity, namely, specificity for the antigenic determinants of pathogens, and the memory of having been exposed to the same pathogen previously, called immunological memory. Implicit in the phenomenon of specificity is the concept of the enormous diversity of the receptor repertoires of lymphocytes. The specificity of immune responses was initially inferred from studies of protective immunity and vaccination against microbes, which was by definition pathogen specific. These early studies culminated in the formulation of the clonal selection hypothesis in the 1950s, which proposed that clones of immunocompetent cells with unique receptors exist prior to exposure to antigens, and only cells with specific receptors are selected by antigen for subsequent activation (Figure 1) (11Burnet F.M The Clonal Selection Theory. Cambridge University Press, London1959Google Scholar). The idea that specificity for diverse antigens exists prior to encounter with these antigens was a radical notion at the time, one that challenged existing concepts of how proteins conformed to the shapes of other interacting proteins. Nevertheless, the clonal selection theory became the foundation for our understanding of the specificity and development of immune responses. The molecular understanding of how the diverse repertoire of antigen receptors is generated came with the studies of Susumu Tonegawa in the 1970s (58Tonegawa S Hozumi N Matthyssens G Schuller R Somatic changes in the content and context of immunoglobulin genes.Cold Spring Harb. Symp. Quant. Biol. 1977; 41: 877-889Crossref PubMed Google Scholar). Based on this work, and its many subsequent refinements, it is now known that the antigen receptors of B and T lymphocytes are encoded by genes that are produced by somatic recombination of gene segments during maturation of the cells. The recombination process is initiated by the RAG proteins, and presence of RAG genes during phylogeny identifies the evolutionary time of appearance of the adaptive immune system, which is just past the appearance of vertebrates (2Agrawal A Eastman Q.M Schatz D.G Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system.Nature. 1998; 394: 744-751Crossref PubMed Scopus (579) Google Scholar, 23Hiom K Melek M Gellert M DNA transposition by the RAG1 and RAG2 proteins a possible source of oncogenic translocations.Cell. 1998; 94: 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). The jawless fish lack RAG genes and lymphoid organs, while cartilaginous fish have RAG genes and a quite well-developed adaptive immune system. Recombination of antigen receptor gene segments serves three critical functions: it allows a vast number of receptors to be generated from a small number of genes, it maximizes the diversity of the receptors by introducing sequence variations at the sites of recombination, and it regulates the development of individual lymphocytes, which is tightly linked to the status of gene rearrangement. Somatic recombination of antigen receptor genes is the paradigm for studying gene rearrangement during cell maturation. Schematic of clonal selection hypothesis illustrating the idea that each naïve lymphocyte has a different receptor specificity, each of which can bind a different antigenic determinant. When a pathogen is recognized by the cells, in this case by two different antigenic determinants, then the cells that bind to these determinants are selected to proliferate or undergo clonal expansion, and then differentiate into effector cells that either secrete antibody or mediate various effector mechanisms of cell-mediated immunity. Immunological memory refers to the ability of the immune system to respond more strongly to successive exposures to the same antigen. The classical definition of memory came from the realization that infection with a particular microbe or vaccination rendered an individual resistant to subsequent exposures to that microbe; that is, they were immune to the specific pathogen. Much effort has been devoted to defining the phenotypic and functional characteristics of memory cells, and much has been learned about what these cells do. However, fundamental questions about the signals that are required to generate memory cells, and the mechanisms responsible for the survival of these cells in the apparent absence of antigen, remain unsolved. This uncertainty is mainly a reflection of the fact that immunological memory has to be studied in vivo, and only recently have methods been developed to identify numerically rare antigen-specific populations in the midst of large numbers of lymphocytes with diverse specificities (4Altman J.D Moss P.A.H Goulder P.J.R Barouch D.H McHeyzer-Williams M.G Bell J.I McMichael A.J Davis M.M Phenotypic analysis of antigen-specific T lymphocytes.Science. 1996; 274: 94-96Crossref PubMed Scopus (3007) Google Scholar, 45Murali-Krishna K Altman J.D Suresh M Sourdive D.J Zajac A.J Miller J.D Slansky J Ahmed R Counting antigen-specific CD8 T cells a reevaluation of bystander activation during viral infection.Immunity. 1998; 8: 177-187Abstract Full Text Full Text PDF PubMed Scopus (1669) Google Scholar, 48Ogg G.S Jin X Bonhoeffer S Dunbar P.R Nowak M.A Monard S Segal J.P Cao Y Rowland-Jones S.L Cerundolo V et al.Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA.Science. 1998; 279: 2103-2106Crossref PubMed Scopus (1233) Google Scholar). The key breakthrough that opened the way for our modern understanding of the immune system was the identification by Jim Gowans of small lymphocytes as the cellular units of clonal selection in adaptive immunity (20Gowans J.L McGregor D.D Cowen D.M Ford C.E Initiation of immune responses by small lymphocytes.Nature. 1962; 196: 651-655Crossref PubMed Scopus (116) Google Scholar). We now know that there are two classes of antigen-specific lymphocytes with receptors for antigens, B and T cells, which function as the mediators of humoral immunity and cell-mediated immunity, respectively. The use of monoclonal antibodies (33Köhler G Milstein C Continuous cultures of fused cells secreting antibody of predefined structure.Nature. 1975; 256: 495-497Crossref PubMed Scopus (12202) Google Scholar) to identify different populations of lymphocytes and to isolate these populations for functional and biochemical analyses has been instrumental in understanding lymphocyte biology. In fact, the ease of producing fairly homogeneous populations of lymphocytes with defined specificities—by purification, cell cloning, and transgenic technology—is the principal reason why lymphocytes have taught us a great deal about fundamental biological phenomena. One of the most impressive accomplishments of immunology is the elucidation of antigen recognition by lymphocytes. We now know that B cell antigen receptors bind a wide variety of macromolecules and small chemicals in different conformations. However, the greatest surprises have come from studies of T cell antigen recognition. This story began with the discovery, in the 1960s and 1970s, that different inbred strains of animals did or did not respond to simple polypeptide antigens, and this immune responsiveness mapped to a highly polymorphic genetic locus that had been discovered as the target of graft rejection and was therefore called the major histocompatibility complex (MHC) (7Benacerraf B McDevitt H.O Histocompatibility-linked immune response genes.Science. 1972; 175: 273-279Crossref PubMed Scopus (802) Google Scholar). These phenomena eluded explanation until, in the mid-1970s, Zinkernagel and Doherty found rather serendipitously that virus-specific CTLs generated in one inbred mouse strain would kill virus-infected target cells only from strains with the same MHC (64Zinkernagel R.M Doherty P.C Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis.Nature. 1974; 251: 547-548Crossref PubMed Scopus (575) Google Scholar). This observation, and the results of experiments examining the interactions of T cells with either B lymphocytes (29Katz D.H Hamaoka T Dorf M.E Maurer P.H Benacerraf B Cell interactions between histoincompatible T and B lymphocytes. IV. Involvement of the immune response (Ir) gene in the control of lymphocyte interactions in responses controlled by the gene.J. Exp. Med. 1973; 138: 734-739Crossref PubMed Scopus (126) Google Scholar) or macrophages (52Rosenthal A.S Shevach E.M Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes.J. Exp. Med. 1973; 138: 1194-1212Crossref PubMed Scopus (664) Google Scholar), ultimately led to the conclusion that in each individual or inbred strain of mouse, T lymphocytes are limited to recognizing foreign protein antigens on the surface of that individual's or strain's own cells, and the key element in antigen recognition by T cells is the MHC. This ability to recognize antigen only in the context of self-MHC molecules is called MHC restricted antigen recognition, or MHC restriction for short. It is now known that MHC molecules expressed on antigen-presenting cells function to display peptides derived from complex proteins to T lymphocytes. Each individual T cell is selected to recognize one or a small number of related peptides bound to one of that individual's 5–15 MHC allelic products (5Babbitt B.P Allen P.M Matsueda G Haber E Unanue E.R Binding of immunogenic peptides to Ia histocompatibility molecules.Nature. 1985; 317: 359-361Crossref PubMed Scopus (917) Google Scholar). As there are over 100 alleles at several loci within the MHC, this means that the MHC is the most polymorphic set of loci within the human genome. The dual specificity of T cells, for peptide antigens and for MHC molecules, led to many theories about how T cells recognized antigens. The great controversy was whether T cells expressed a single receptor that saw both peptide and MHC, or one receptor for each. Early studies showed that fusing two distinct T cell lines did not generate four different specificities, as predicted by the dual specificity model, but rather the two original specificities of the parent clones, as would be predicted from the single receptor hypothesis (28Kappler J.W Skidmore B White J Marrack P Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition.J. Exp. Med. 1981; 153: 1198-1214Crossref PubMed Scopus (882) Google Scholar). Biochemical analyses of the T cell antigen receptor also showed a single receptor molecule, but the identification of the T cell receptor (TCR) for antigen came from molecular cloning (22Hendrick S.M Cohen D.I Neilsen E.A Davis M.M Isolation of cDNA clones encoding T cell–specific membrane-associated proteins.Nature. 1984; 308: 149-153Crossref PubMed Scopus (858) Google Scholar). The definitive results that established the structural basis of MHC restriction came with the solution of the crystal structure of MHC molecules, which showed that these molecules contained bound peptides (10Bjorkman P.J Saper M.A Samraoui B Bennett W.S Strominger J.L Wiley D.C Structure of the human class I histocompatibility antigen, HLA-A2.Nature. 1987; 329: 506-512Crossref PubMed Scopus (2668) Google Scholar) (Figure 2), and ultimately in the solution of the crystal structures of T cell receptors binding to MHC: peptide complexes (Figure 2) (16Garboczi D.N Ghosh P Utz U Fan Q.R Biddison W.E Wiley D.C Structure of the complex between human T-cell receptor, viral peptide and HLA-A2.Nature. 1996; 384: 134-141Crossref PubMed Scopus (1173) Google Scholar, 17Garcia K.C Degano M Stanfield R.L Brunmark A Jackson M.R Peterson P.A Teyton L Wilson I.A An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex.Science. 1996; 274: 209-219Crossref PubMed Scopus (1033) Google Scholar). These remain among the most informative crystal structures ever defined because they revealed in fine detail the basis for one of the puzzling features of antigen recognition. A great surprise from these structural results, which confirm previous data based on mutational analyses of peptides, is that each TCR recognizes very few residues of the MHC-associated peptide. Taken together with the established idea that even in complex microbes, only a few peptides are recognized by the immune system, this means that T cells are able to distinguish between different microbes on the basis of very few differences in amino acid sequences. How this remarkable specificity is maintained despite the enormous structural diversity of microbes remains a fascinating question. In parallel with these structural studies of the MHC, cell biologists dissected the mechanisms of antigen uptake, processing, and presentation. The key conclusion of these studies is that the two classes of MHC molecules function to sample protein antigens from different cellular compartments and display these antigens for recognition by different classes of T cells. Protein antigens located in the cytosol are processed by proteasomes, translocated into the endoplasmic reticulum, and displayed by MHC class I molecules for recognition by CD8 T cells. Thus, MHC class I molecules can alert CD8 T cells to the presence of foreign antigens, such as viral and tumor antigens, that are synthesized within infected or transformed cells, leading to the elimination of these cells. By contrast, extracellular pathogens and proteins that are internalized into the vesicles of phagocytes are processed by vesicular proteases and displayed bound to MHC class II molecules for recognition by CD4 T cells (46Nakagawa T.Y Brissette W.H Lira P.D Griffiths R.J Petrushova N Stock J McNeish J.D Eastman S.E Howard E.D Clarke S.R et al.Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice.Immunity. 1999; 10: 207-217Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar). The elucidation of the peptide display function of MHC molecules has solved two fundamental problems in immunology. The first is how the immune system ensures that T cells, designed to combat intracellular microbes, are the cells of cell-mediated immunity. The answer to this is that because the MHC molecules that display peptides are integral membrane proteins, T cells can only see antigens bound to other cells, and these are the antigens of intracellular or phagocytosed microbes. The second is how the immune system knows that it should make antibodies against extracellular microbes but trigger the effector mechanisms of cell-mediated immunity, such as T cell–mediated killing of infected cells, after microbes have found a haven inside host cells. This problem was especially puzzling because humoral and cell-mediated immune responses can be generated against the same microbe, such as a virus, at different stages of its life, i.e., extracellular and intracellular, respectively. The answer is that MHC molecules instruct the immune system on how to respond by segregating the antigens of vesicular and cytosolic antigens in such a way that they are recognized by different classes of T cells—helper cells that stimulate antibody production and CTLs that kill infected cells, respectively. The realizations that very few lymphocytes out of the total population recognize any one antigen, very few peptides derived from any microbe are recognized by the immune system, and very few MHC molecules on APCs display any one peptide have highlighted what appears to be an insurmountable logistical problem—how do we ever get effective immune responses against microbes? This problem is largely handled by a specialized population of professional antigen-presenting cells (APCs), the dendritic cells (DCs), which are strategically located under the skin and the mucosal epithelia—common sites of contact with the external environment (6Banchereau J Steinman R.M Dendritic cells and the control of immunity.Nature. 1998; 392: 245-252Crossref PubMed Scopus (11831) Google Scholar). Immature DCs are highly phagocytic and are designed to capture microbial antigens in the periphery. They then migrate to the T cell–rich areas of local lymph nodes, where, as mature DCs, they express high levels of MHC-associated peptides derived from the pathogen. The migration is not a random process and is tightly regulated by chemokines produced in the lymph nodes, for which dendritic cells express specific receptors (41Melchers F Rolink A.G Schaniel C The role of chemokines in regulating cell migration during humoral immune responses.Cell. 1999; 99: 351-354Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Once in the lymph node, DCs also begin to express molecules that are necessary to activate the naïve T cells that continuously flow through the same areas of the lymph node. Thus, the rare antigen-specific T cells come in contact with antigen-loaded dendritic cells, leading to the initiation of lymphocyte responses. Overall, our present understanding of anitgen presentation to T lymphocytes provides one of the best examples of how immunologists, biochemists, cell biologists, and morphologists can come together to attack a complex problem (12Cresswell P Assembly, transport, and function of MHC class II molecules.Annu. Rev. Immunol. 1994; 12: 259-293Crossref PubMed Google Scholar, 18Germain R.N MHC-dependent antigen processing and peptide presentation providing ligands for T lymphocyte activation.Cell. 1994; 76: 287-299Abstract Full Text PDF PubMed Scopus (1240) Google Scholar). Innate immunity provides early host defense against infections, before the development of an adaptive immune response. Innate immune responses of marine starfish were discovered by Elie Metchnikoff in the late 1800s, and this work remains a cornerstone in the study of various aspects of innate immunity (42Metchnikoff E Lectures on the comparative pathology of inflammation. Kegan, Paul, Trench, Trubner, London1893Google Scholar). Innate immunity is mediated by cells, such as phagocytes and natural killer cells, circulating proteins, such as the complement system, and numerous anti-microbial peptides. These components use germline-encoded “pattern recognition receptors” to recognize molecular structures, or “patterns,” present on various classes of microbes. Many of these receptors, such as the Toll family of proteins, are conserved throughout evolution and serve the same function of anti-microbial defense in all multicellular organisms, including plants. Innate immunity also stimulates adaptive immune responses (40Medzhitov R Preston-Hurlburt P Janeway Jr., C.A A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Nature. 1997; 388: 394-397Crossref PubMed Scopus (4208) Google Scholar). This realization has explained some fundamental features of adaptive immunity and is discussed in more detail below. The survival and functional responses of lymphocytes are regulated by cell–cell interactions and by an orchestrated interplay of positive and negative signals. All adaptive immune responses are dependent on the activation of antigen-specific lymphocytes, and this process is triggered by binding of antigen to the lymphocyte receptors. To ensure that immune responses develop only when they are needed, i.e., when there is an infection, naïve lymphocytes need at least two signals to be fully activated to proliferate and differentiate. The first signal is provided by specific antigen recognition. By itself, this signal can fail to stimulate a response or can induce a state of inactivity referred to as clonal anergy, the inability to respond to antigen (56Schwartz R.H Costimulation of T lymphocytes the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy.Cell. 1992; 71: 1065-1068Abstract Full Text PDF PubMed Scopus (1201) Google Scholar) (Figure 3). However, when the antigen is delivered as part of a pathogen, the second signal is provided by innate immune responses to microbes or, in some cases, by the pathogen itself (40Medzhitov R Preston-Hurlburt P Janeway Jr., C.A A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Nature. 1997; 388: 394-397Crossref PubMed Scopus (4208) Google Scholar). This requirement for second signals explains why adaptive immune responses are stimulated by microbes but not by most self-antigens, which are not normally recognized by the innate immune system and therefore do not elicit adaptive immune responses. Adjuvants are required to stimulate adaptive immune responses to protein antigens, and the key constituents in these adjuvants are microbial products, which function by stimulating innate immunity (25Janeway Jr., C.A Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harb. Symp. Quant. Biol. 1989; 54: 1-13Crossref PubMed Google Scholar). The best defined second signals for T cells are the costimulatory molecules known as B7-1 (CD80) and B7-2 (CD86) (21Harding F.A McArthur J.G Gross J.A Raulet D.H Allison J.P CD28-mediated signaling co-stimulates murine T cells and prevents induction of anergy in T-cell clones.Nature. 1992; 356: 607-609Crossref PubMed Scopus (1452) Google Scholar, 37Linsley P.S Ledbetter J.A The role of the CD28 receptor during T cell responses to antigen.Annu. Rev. Immunol. 1993; 11: 191-212Crossref PubMed Scopus (1193) Google Scholar). These molecules are only expressed on professional APCs, and their expression peaks after the APCs are activated by microbial products. Activated APCs also produce cytokines during innate immune reactions, which further stimulate T cell responses. The B7 proteins are recognized by the CD28 receptor, which is expressed on most naïve T cells, especially those of the CD4 subset. Together with the antigen receptor signal (signal 1), recognition of B7 proteins by CD28 leads to T cell activation, clonal expansion, and the development of effector T cell function (Figure 3). Activated T cells express a molecule called CD40 ligand (CD40L), which has several functions. One of these is to activate APCs to increase expression of B7 costimulators and to stimulate production of cytokines, such as IL-12, that induce the differentiation of T cells. Thus, CD40L serves to amplify T cell proliferation and differentiation into effector cells. The identification of second signals for lymphocyte activation has led to the development of a new class of agents that inhibit immune responses by blocking these signals. Antagonists against B7 molecules and CD40 ligand are currently in clinical trials for inhibiting graft rejection and for treating some hypersensitivity and autoimmune disorders (15Foy T.M Aruffo A Bajorath J Buhlmann J.E Noelle R.J Immune regulation by CD40 and its ligand GP39.Annu. Rev. Immunol. 1996; 14: 591-617Crossref PubMed Scopus (563) Google Scholar, 39Markees T.G Phillips N.E Gordon E.J Noelle R.J Shultz L.D Mordes J.P Greiner D.L Rossini A.A Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4(+) T cells, interferon-gamma, and CTLA4.J. Clin. Invest. 1998; 101: 2446-2455Crossref PubMed Scopus (250) Google Scholar, 30Kenyon N.S Chatzipetrou M Masetti M Ranuncoli A Oliveira M Wagner J.L Kirk A.D Harlan D.M Burkly L.C Ricordi C Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154.Proc. Natl. Acad. Sci. USA. 1999; 96: 8132-8137Crossref PubMed Scopus (364) Google Scholar, 32Kirk A.D Burkly L.C Batty D.S Baumgartner R.E Berning J.D Buchanan K Fechner Jr., J.H Germond R.L Kampen R.L Patterson N.B et al.Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates.Nat. Med. 1999; 5: 686-693Crossref PubMed Scopus (721) Google Scholar). The story is very much an evolving one because new costimulators and their receptors continue to be discovered. What is needed is an integrated picture of when the individual costimulators are active during immune responses, what types of responses they stimulate, and how they signal T cells. Effector T cells can respond to antigen in the absence of costimulators and thus are able to interact with many cell types that express microbial antigens. They function by altering the behavior of their targets. MHC class I–restricted CD8 effector T cells can attack virtually any cell in the body, as most cells express MHC class I molecules. MHC class II–restricted CD4 T cells can only interact with cells that express MHC class II molecules, such as macrophages carrying pathogens or B cells that bind specific antigens. The functions of effector T cells are described in more detail later. The molecules that mediate cell–cell interactions are better defined in the immune system than in any other biological system (13Dustin M.L Olszowy M.W Holdorf A.D Li J Bromley S Desai N Widder P Rosenberger F van der Merwe P.A Allen P.M Shaw A.S A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts.Cell. 1998; 94: 667-677Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar). This knowledge has given immunologists valuable tools for analyzing the processes of T cell–APC and T cell–B cell interactions in considerable detail. Recent studies have shown that various surface molecules of T cells undergo rapid reorientation upon antigen recognition, with antigen receptors and their associated signal-transducing subunits aggregating in the central regions of membrane microdomains, and adhesion molecules forming peripheral rings around these clustered receptors (13Dustin M.L Olszowy M.W Holdorf A.D Li J Bromley S Desai N Widder P Rosenberger F van der Merwe P.A Allen P.M Shaw A.S A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts.Cell. 1998; 94: 667-677Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar, 43Monks C.R Freiberg B.A Kupfer H Sciaky N Kupfer A Three-dimensional segregation of supramolecular activation clusters in T cells.Nature. 1998; 395: 82-86Crossref PubMed Scopus (1896) Google Scholar). These molecular aggregates have been called supramolecular activation complexes, or immunological synapses, and some of them lie in lipid rafts on the cell surface. Presumably, aggregation of antigen receptors brings sufficient receptor-associated signaling molecules into proximity to achieve the threshold needed to trigger cellular responses. The signaling molecules include a number of adapter proteins, kinases, and their substrates. How the receptors are aggregated in a particular topology upon binding to their cognate ligand remains a mystery, and this issue is likely to be one of interest to all biologists interested in the problem of how cells sense and respond to other cells and external stimuli. Recent studies using the BIAcore suggest that T cell receptors change their shape upon binding antigen and form aggregates on the cell surface (3Alam S.M Davies G.M Lin C.M Zal T Nasholds W Jameson S.C Hogquist K.A Gascoigne N.R Travers P.J Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands.Immunity. 1999; 10: 227-237Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). The general rules of signal transduction in lymphocytes are probably fundamentally similar to those in other cells, using common response pathways such as increases in intracellular calcium, activation of kinase cascades, and activation of the mitogen activated kinases (62Weiss A Littman D.R Signal transduction by lymphocyte antigen receptors.Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1921) Google Scholar). The culmination of these signaling cascades is translocation of activated transcription factors into the cell nucleus, resulting in the expression of genes that encode c