Annual Review of Immunology - Volume 24, 2006

After starting out to become a physician, by a series of accidents I found myself at NIH in 1951 during its most productive growth phase. At age 26, I had a fully funded, independent laboratory and did not know what to work on. With advice from colleagues, I initiated a study of how penicillin kills bacteria. Twenty years later, my lab had outlined the structure and biosynthesis of the peptidoglycan of bacterial cell walls and had discovered that penicillin inhibited the terminal step in its biosynthesis catalyzed by transpeptidases. I then switched fields, moving to Harvard in 1968 and beginning the study of human HLA proteins. Twenty-five years later, the last half of which was spent in a stimulating collaboration with the late Don Wiley, our labs had isolated, crystallized, and elucidated the three-dimensional structures of these molecules and shown that their principal function was to present peptides to the immune system in initiating an immune response. More recently, the laboratory has focused on natural killer cells and their roles in peripheral blood and in the pregnant uterine decidua. It has been a wonderful scientific journey.

Studies of bone and the immune system have converged in recent years under the banner of osteoimmunology. The immune system is spawned in the bone marrow reservoir, and investigators now recognize that important niches also exist there for memory lymphocytes. At the same time, various factors produced during immune responses are capable of profoundly affecting regulation of bone. Mechanisms have evolved to prevent excessive interference by the immune system with bone homeostasis, yet pathologic bone loss is a common sequela associated with autoimmunity and cancer. There are also developmental links, or parallels, between bone and the immune system. Cells that regulate bone turnover share a common precursor with inflammatory immune cells and may restrict themselves anatomically, in part by utilizing a signaling network analogous to lymphocyte costimulation. Efforts are currently under way to further characterize how these two organ systems overlap and to develop therapeutic strategies that benefit from this understanding.

Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules' potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design immunotherapeutic agents that target CTLA-4.

Transforming growth factor-β (TGF-β) is a potent regulatory cytokine with diverse effects on hemopoietic cells. The pivotal function of TGF-β in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-β controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis, activation, and survival of lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. The regulatory activity of TGF-β is modulated by the cell differentiation state and by the presence of inflammatory cytokines and costimulatory molecules. Collectively, TGF-β inhibits the development of immunopathology to self or nonharmful antigens without compromising immune responses to pathogens. This review highlights the findings that have advanced our understanding of TGF-β in the immune system and in disease.

Eosinophils have been considered end-stage cells involved in host protection against parasites. However, numerous lines of evidence have now changed this perspective by showing that eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, we summarize the biology of eosinophils, focusing on the growing properties of eosinophil-derived products, including the constituents of their granules as well as the mechanisms by which they release their pleiotropic mediators. We examine new views on the role of eosinophils in homeostatic function, including developmental biology and innate and adaptive immunity (as well as interaction with mast cells and T cells). The molecular steps involved in eosinophil development and trafficking are described, with special attention to the important role of the transcription factor GATA-1, the eosinophil-selective cytokine IL-5, and the eotaxin subfamily of chemokines. We also review the role of eosinophils in disease processes, including infections, asthma, and gastrointestinal disorders, and new data concerning genetically engineered eosinophil-deficient mice. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.

Many antigens recognized by autologous T lymphocytes have been identified on human melanoma. Melanoma patients usually mount a spontaneous T cell response against their tumor. But at some point, the responder T cells become ineffective, probably because of a local immunosuppressive process occurring at the tumor sites. Therapeutic vaccination of metastatic melanoma patients with these antigens is followed by tumor regressions only in a small minority of the patients. The T cell responses to the vaccines show correlation with the tumor regressions. The local immunosuppression may be the cause of the lack of vaccination effectiveness that is observed in most patients. In patients who do respond to the vaccine, the antivaccine T cells probably succeed in reversing focally this immunosuppression and trigger a broad activation of other antitumor T cells, which proceed to destroy the tumor.

The immune system has evolved mechanisms to recognize and eliminate threats, as well as to protect against self-destruction. Tolerance to self-antigens is generated through two fundamental mechanisms: (a) elimination of self-reactive cells in the thymus during selection and (b) generation of a variety of peripheral regulatory cells to control self-reactive cells that escape the thymus. It is becoming increasing apparent that a population of thymically derived CD4⁺ regulatory T cells, exemplified by the expression of the IL-2Rα chain, is essential for the maintenance of peripheral tolerance. Recent work has shown that the forkhead family transcription factor Foxp3 is critically important for the development and function of the regulatory T cells. Lack of Foxp3 leads to development of fatal autoimmune lymphoproliferative disease; furthermore, ectopic Foxp3 expression can phenotypically convert effector T cells to regulatory T cells. This review focuses on Foxp3 expression and function and highlights differences between humans and mice regarding Foxp3 regulation.

A prophylactic vaccine for HIV-1 is badly needed. Despite 20 years of effort, it is still a long way off. However, considerable progress has been made in understanding the problem. The virus envelope has evolved to evade neutralizing antibodies in an extraordinary way, yet a vaccine that can stimulate such antibodies remains the best hope. Anti-HIV-1 T cell responses are evaded by continuous mutation of the virus. Vaccine strategies that concentrate on stimulating T cell immunity will at best generate broadly reactive and persisting T cell responses that can suppress virus without preventing infection, limiting or preventing the damage the virus causes. The SIV macaque models give encouragement that this is possible, but they need further understanding. Therapeutic vaccination should also be considered.

NK cells sit at the crossroads of innate and adaptive immunity and help coordinate tumor immunosurveillance and the immune response against pathogens. Balancing signals to NK cell precursors is crucial for their early development, when transcription factors compete to specify the different lymphocyte subsets. Despite an elaborate schema for NK cell development and differentiation, several major issues remain to be addressed, such as identifying the sites for NK cell maturation and defining the peripheral NK cell niche.

The lymphocytes, T, B, and NK cells, and a proportion of dendritic cells (DCs) have a common developmental origin. Lymphocytes develop from hematopoietic stem cells via common lymphocyte and various lineage-restricted precursors. This review discusses the current knowledge of human lymphocyte development and the phenotypes and functions of the rare intermediate populations that together form the pathways of development into T, B, and NK cells and DCs. Clearly, development of hematopoietic cells is supported by cytokines. The studies of patients with genetic deficiencies in cytokine receptors that are discussed here have illuminated the importance of cytokines in lymphoid development. Lineage decisions are under control of transcription factors, and studies performed in the past decade have provided insight into transcriptional control of human lymphoid development, the results of which are summarized and discussed in this review.

Human genetics offers new possibilities for understanding physiological regulatory mechanisms and disorders of the immune system. Genetic abnormalities of lymphocyte cell death programs have provided insights into mechanisms of receptor biology and principles of immune homeostasis and tolerance. Thus far, there are two major diseases of programmed cell death associated with inherited human mutations: the autoimmune lymphoproliferative syndrome and the caspase-eight deficiency state. We describe the details of their molecular pathogenesis and discuss how these diseases illustrate important concepts in immune regulation and genetics.

Classical genetic methods, driven by phenotype rather than hypotheses, generally permit the identification of all proteins that serve nonredundant functions in a defined biological process. Long before this goal is achieved, and sometimes at the very outset, genetics may cut to the heart of a biological puzzle. So it was in the field of mammalian innate immunity. The positional cloning of a spontaneous mutation that caused lipopolysaccharide resistance and susceptibility to Gram-negative infection led directly to the understanding that Toll-like receptors (TLRs) are essential sensors of microbial infection. Other mutations, induced by the random germ line mutagen ENU (N-ethyl-N-nitrosourea), have disclosed key molecules in the TLR signaling pathways and helped us to construct a reasonably sophisticated portrait of the afferent innate immune response. A still broader genetic screen—one that detects all mutations that compromise survival during infection—is permitting fresh insight into the number and types of proteins that mammals use to defend themselves against microbes.

Several proteomics platforms have emerged in the past decade that show great promise for filling in the many gaps that remain from earlier studies of the genome and from the sequencing of the human genome itself. This review describes applications of proteomics technologies to the study of autoimmune diseases. We focus largely on biased technology platforms that are capable of analyzing a large panel of known analytes, as opposed to techniques such as two-dimensional gel electrophoresis (2DIGE) or mass spectroscopy that represent unbiased approaches (as reviewed in 1). At present, the main analytes that can be systematically studied in autoimmunity include autoantibodies, cytokines and chemokines, components of signaling pathways, and cell-surface receptors. We review the most commonly used platforms for such studies, citing important discoveries and limitations that exist. We conclude by reviewing advances in biomedical informatics that will eventually allow the human proteome to be deciphered.

Since the first crystal structure determinations of αβ T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound γδ TCR structures has enabled comparisons of the modes of antigen recognition by αβ and γδ T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3εδ, CD3εγ) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.

The pathogenic roles of B cells in autoimmune diseases occur through several mechanistic pathways that include autoantibodies, immune complexes, dendritic and T cell activation, cytokine synthesis, chemokine-mediated functions, and ectopic neolymphogenesis. Each of these pathways participate to different degrees in autoimmune diseases. The use of B cell–targeted and B cell subset–targeted therapies in humans is illuminating the mechanisms at work in a variety of human autoimmune diseases. In this review, we highlight some of these recent findings that provide insights into both murine models of autoimmunity and human autoimmune diseases.

Approximately 500 mya two types of recombinatorial adaptive immune systems appeared in vertebrates. Jawed vertebrates generate a diverse repertoire of B and T cell antigen receptors through the rearrangement of immunoglobulin V, D, and J gene fragments, whereas jawless fish assemble their variable lymphocyte receptors through recombinatorial usage of leucine-rich repeat (LRR) modular units. Invariant germ line–encoded, LRR-containing proteins are pivotal mediators of microbial recognition throughout the plant and animal kingdoms. Whereas the genomes of plants and deuterostome and chordate invertebrates harbor large arsenals of recognition receptors primarily encoding LRR-containing proteins, relatively few innate pattern recognition receptors suffice for survival of pathogen-infected nematodes, insects, and vertebrates. The appearance of a lymphocyte-based recombinatorial system of anticipatory immunity in the vertebrates may have been driven by a need to facilitate developmental and morphological plasticity in addition to the advantage conferred by the ability to recognize a larger portion of the antigenic world.

Concepts of cell-cell interactions in adaptive immunity have alternated between the simple and the complex. The notion that one population of small, circulating lymphocytes is responsible for adaptive immunity was sequentially supplanted by the concept of separate T and B lymphocyte populations that cooperate to produce IgG antibody responses, by a three-cell model in which a myeloid APC initiates these cooperative lymphoid responses, by the recognition of T cell subsets, and by the idea that CD8⁺ T cell subset responses to graft antigens depend on CD4⁺ T cell subset activity. Simplicity was reintroduced with the revelation that CD8⁺ T cells can act independently of CD4⁺ T cells against acute viral infections. The pendulum has swung again toward complexity with recognition of the distinct and conjoint contributions of innate stimuli, APCs, NK and NKT cells, Tregs, and CD4⁺ helper T cells to CD8⁺ T cell behavior during acute and chronic infections or as memory cells. The renewed appreciation that multiple, sometimes rare cell types must communicate during cell-mediated immune responses has led to questions about how such interactions are orchestrated within organized lymphoid tissues. We review recent advances in deciphering the specific contribution of CD4⁺ T cells to physiologically useful CD8⁺ T cell responses, the signals involved in producing acute effectors versus long-lived memory cells, and the mechanisms underlying the cell-cell associations involved in delivery of such signals. We propose a model based on these new findings that may serve as a general paradigm for cellular interactions that occur in an inflamed lymph node during the initiation of immune responses.

V(D)J recombination assembles antigen receptor variable region genes from component germline variable (V), diversity (D), and joining (J) gene segments. For B cells, such rearrangements lead to the production of immunoglobulin (Ig) proteins composed of heavy and light chains. V(D)J is tightly controlled at the Ig heavy chain locus (IgH) at several different levels, including cell-type specificity, intra- and interlocus ordering, and allelic exclusion. Such controls are mediated at the level of gene segment accessibility to V(D)J recombinase activity. Although much has been learned, many long-standing questions regarding the regulation of IgH locus rearrangements remain to be elucidated. In this review, we summarize advances that have been made in understanding how V(D)J recombination at the IgH locus is controlled and discuss important areas for future investigation.

Recent elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmatic shift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissues of the body, irrespective of developmental or spatio-temporal expression patterns. This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.

Helper T cells coordinate immune responses through the production of cytokines. Th2 cells express the closely linked Il4, Il13, and Il5 cytokine genes, whereas these same genes are silenced in the Th1 lineage. The Th1/Th2 lineage choice has become a textbook example for the regulation of cell differentiation, and recent discoveries have further refined and expanded our understanding of how Th2 differentiation is initiated and reinforced by signals from antigen-presenting cells and cytokine-driven feedback loops. Epigenetic changes that stabilize the active or silent state of the Il4 locus in differentiating helper T cells have been a major focus of recent research. Overall, the field is progressing toward an integrated model of the signaling and transcription factor networks, cis-regulatory elements, epigenetic modifications, and RNA interference mechanisms that converge to determine the lineage fate and gene expression patterns of differentiating helper T cells.