Annual Review of Immunology - Volume 25, 2007

My research career has focused on complex experimental systems, principally virus-induced infectious processes. I have always run my own experimental program and never had a major mentor, although I have had many great colleagues. After graduating from the School of Veterinary Science at the University of Queensland, Australia, I worked for nine years on diseases of domestic animals. During that interval I completed a part-time PhD at the University of Edinburgh while employed as an experimental neuropathologist. Returning to the John Curtin School of Medical Research in Canberra, I focused on cell-mediated immunity, started to work seriously with mice, and thus became both an immunologist and a basic medical scientist. It was there in 1973 that Rolf Zinkernagel and I discovered MHC I–restricted CD8⁺ T cell recognition, a finding that, together with the “single T cell receptor/altered self” hypothesis that we developed to explain our results, led to the 1996 Nobel Prize for Physiology or Medicine. Part of my focus since then has been to communicate the societal value and power of science to the broader community. As my scientific life is not yet over, I confine the present historical account to the twentieth century.

Immunoglobulins are the major secretory products of the adaptive immune system. Each is characterized by a distinctive set of glycoforms that reflects the wide variation in the number, type, and location of their oligosaccharides. In a given physiological state, glycoform populations are reproducible; therefore, disease-associated alterations provide diagnostic biomarkers (e.g., for rheumatoid arthritis) and contribute to disease pathogenesis. The oligosaccharides provide important recognition epitopes that engage with lectins, endowing the immunoglobulins with an expanded functional repertoire. The sugars play specific structural roles, maintaining and modulating effector functions that are physiologically relevant and can be manipulated to optimize the properties of therapeutic antibodies. New molecular models of all the immunoglobulins are included to provide a basis for informed and critical discussion. The models were constructed by combining glycan sequencing data with oligosaccharide linkage and dynamics information from the Glycobiology Institute experimental database and protein structural data from “The Protein Data Bank.”

Bone remodeling by bone-forming osteoblasts and bone-resorbing osteoclasts dynamically alters the bone inner wall and the endosteum region, which harbors osteoblastic niches for hematopoietic stem cells. Investigators have recently elucidated mechanisms of recruitment and mobilization; these mechanisms consist of stress signals that drive migration of leukocytes and progenitor cells from the bone marrow reservoir to the circulation and drive their homing to injured tissues as part of host defense and repair. The physical bone marrow vasculature barrier that is crossed by mobilized cells actively transmits chemotactic signals between the blood and the bone marrow, facilitating organ communication and cell trafficking. Osteoclasts play a dual role in regulation of bone resorption and homeostatic release or stress-induced mobilization of hematopoietic stem/progenitor cells. In this review, we discuss the orchestrated interplay between bone remodeling, the immune system, and the endosteal stem cell niches in the context of stem cell proliferation and migration during homeostasis, which are accelerated during alarm situations.

The hepatitis C virus (HCV) is a remarkably successful pathogen, establishing persistent infection in more than two-thirds of those who contract it. Its success is related to its abilities to blunt innate antiviral pathways and to evade adaptive immune responses. These two themes may be related. We propose that HCV takes advantage of the impaired innate response to delay the organization of an effective adaptive immune attack. The tolerogenic liver environment may provide cover, prolonging this delay. HCV's error-prone replication strategy permits rapid evolution under immune pressure. Persistent high levels of viral antigens may contribute to immune exhaustion. Finally, the virus may benefit from the efficient enlistment of memory T and B cells in the pursuit of a moving target.

Resolution of inflammation and the return of tissues to homeostasis are essential. Efforts to identify molecular events governing termination of self-limited inflammation uncovered pathways in resolving exudates that actively generate, from essential omega fatty acids, new families of local-acting mediators. These chemical mediator families, termed resolvins and protectins, are potent stereoselective agonists that control the duration and magnitude of inflammation, joining the lipoxins as signals in resolution. This review examines the mapping of these circuits and recent advances in our understanding of the biosynthesis and actions of these novel proresolving lipid mediators. Aspirin jump-starts resolution by triggering biosynthesis of specific epimers of these mediators. In addition to their origins in inflammation resolution, these compounds also display potent protective roles in neural systems, liver, lung, and eye. Given the potent actions of lipoxins, resolvins, and protectins in models of human disease, deficiencies in resolution pathways may contribute to many diseases and offer exciting new potential for therapeutic control via resolution.

Allogeneic hematopoietic stem cell transplantation (HSCT) has evolved into an effective adoptive cellular immunotherapy for the treatment of a number of cancers. The immunobiology of allogeneic HSCT is unique in transplantation in that it involves potential immune recognition and attack between both donor and host. Much of the immunobiology of allogeneic HSCT has been gleaned from preclinical models and correlation with clinical observations. We review our current understanding of some of the issues that affect the success of this therapy, including host-versus-graft (HVG) reactions, graft-versus-host disease (GVHD), graft-versus-tumor (GVT) activity, and restoration of functional immunity to prevent transplant-related opportunistic infections. We also review new strategies to optimize the GVT and improve overall immune function while reducing GVHD and graft rejection.

Technological advances in recent years have allowed for an ever-expanding ability to analyze and quantify in vivo immune responses. MHC tetramers, intracellular cytokine staining, an increasing repertoire of transgenic and “knockout” mice, and the detailed characterization of a variety of infectious models have all facilitated more precise and definitive analyses of the generation and function of cytotoxic T lymphocytes (CTL). Understanding the mechanisms behind the differentiation of effector and memory CTL is of increasing importance to develop vaccination strategies against a variety of established and emerging infectious diseases. This review focuses on recent advances in our understanding of how effector and memory CTL differentiate and survive in vivo in response to viral or bacterial infection.

Dendritic cells (DCs) are professional antigen-presenting cells that have the ability to sense infection and tissue stress, sample and present antigen to T lymphocytes, and induce different forms of immunity and tolerance. The functional versatility of DCs depends on their remarkable ability to translate collectively the information from both the invading microbes and their resident tissue microenvironments and then make an appropriate immune response. Recent progress in understanding TLR biology has illuminated the mechanisms by which DCs link innate and adaptive antimicrobial immune responses. However, how tissue microenvironments shape the function of DCs has remained elusive. Recent studies of TSLP (thymic stromal lymphopoietin), an epithelial cell–derived cytokine that strongly activates DCs, provide evidence at a molecular level that epithelial cells/tissue microenvironments directly communicate with DCs. We review recent progress on how TSLP expressed within thymus and peripheral lymphoid and nonlymphoid tissues regulates DC-mediated central tolerance, peripheral T cell homeostasis, and inflammatory Th2 responses.

Long-term resistance to many infections depends on the innate ability of the immune system to coordinate the development of antigen-specific adaptive responses. Deficiencies in these events can result in increased susceptibility to pathogens, whereas an inability to regulate an appropriate response can lead to devastating pathological conditions. For over a decade, interleukin (IL)-12 has been recognized as the canonical cytokine that links innate and adaptive immunity, and with the discovery of IL-23 and IL-27 as cytokines related to IL-12, there has been a concerted effort to understand the relationship between these factors. The results emerging from these studies have provided fundamental new insights into the developmental pathways that promote the differentiation and function of CD4⁺ T helper cells and offer a dramatically altered perspective on the cause and prevention of autoimmune disease. In this review, we aim to highlight the discoveries that have led to our current understanding of the biology of IL-23 and IL-27 in the context of their role in resistance to infection, immune-mediated inflammation, and cancer.

Adoptive transfer of antigen-specific T lymphocytes is a powerful therapy for the treatment of opportunistic disease and some virus-associated malignancies such as Epstein-Barr virus–positive post-transplant lymphoproliferative disease. However, this strategy has been less successful in patients with nonviral cancers owing to their many and varied immune evasion mechanisms. These mechanisms include downregulation of target antigens and antigen-presenting machinery, secretion of inhibitory cytokines, and recruitment of regulatory immune cells to the tumor site. With increased understanding of the tumor microenvironment and the behavior and persistence of ex vivo–manipulated, adoptively transferred T cells, two novel approaches for increasing the efficacy of T cell therapy have been proposed. The first involves genetic modification of tumor-specific T cells to improve their biological function, for example by augmenting their ability to recognize tumor cells or their resistance to tumor-mediated immunosuppression. The second requires modifications to the host environment to improve the homeostatic expansion of infused T cells or to eliminate inhibitory T cell subsets. In this review, we discuss current, promising strategies to improve adoptive T cell therapy for the treatment of cancer.

Despite major advances in understanding the mechanisms leading to tumor immunity, a number of obstacles hinder the successful translation of mechanistic insights into effective tumor immunotherapy. Such obstacles include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, the activation of negative costimulatory signals, and the elaboration of immunosuppressive factors. In addition, we underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network; these include regulatory T cells, natural killer T cells, and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms may be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression.

Recognized more than a decade ago, NKT cells differentiate from mainstream thymic precursors through instructive signals emanating during TCR engagement by CD1d-expressing cortical thymocytes. Their semi-invariant αβ TCRs recognize isoglobotrihexosylceramide, a mammalian glycosphingolipid, as well as microbial α-glycuronylceramides found in the cell wall of Gram-negative, lipopolysaccharide-negative bacteria. This dual recognition of self and microbial ligands underlies innate-like antimicrobial functions mediated by CD40L induction and massive Th1 and Th2 cytokine and chemokine release. Through reciprocal activation of NKT cells and dendritic cells, synthetic NKT ligands constitute promising new vaccine adjuvants. NKT cells also regulate a range of immunopathological conditions, but the mechanisms and the ligands involved remain unknown. NKT cell biology has emerged as a new field of research at the frontier between innate and adaptive immunity, providing a powerful model to study fundamental aspects of the cell and structural biology of glycolipid trafficking, processing, and recognition.

SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell–dependent humoral immune responses, NK cell–mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states.

The internal surfaces of the human body are covered by distinct types of epithelial cells and mucus-secreting cells. The mucosal surfaces serve many vital functions, such as respiration (nasal passage and lung), absorption (gastrointestinal tract), excretion (lung, urinary tract, large intestine), and reproduction (reproductive tract). In performing these functions, the host is inevitably exposed to environmental antigens, food particles, commensal flora, and pathogens. Mucosal surfaces contain specialized dendritic cells (DCs) capable of sensing these external stimuli and mounting appropriate local responses depending on the nature of the elements they encounter. In the absence of pathogens, mucosal DCs either ignore the antigen or induce regulatory responses. Upon recognition of microorganisms that invade the mucosal barrier, mucosal DCs mount robust protective immunity. This review highlights progress in our understanding of how mucosal DCs process external information and direct appropriate responses by mobilizing various cells of the innate and adaptive immune systems to achieve homeostasis and protection.

Pattern recognition receptors (PRRs), expressed on cells of both the innate and adaptive immune systems, serve as sentinels, waiting to alert the host to the first signs of microbial infection and to activate the initial line of immune defense. Research has increasingly demonstrated that many of the same PRRs also recognize self-epitopes that either are released from dying or damaged cells or are present at the surface of apoptotic cells or apoptotic bodies. In this context, PRRs play a critical role in tissue repair and the clearance of cellular debris. However, failure to appropriately regulate self-responses triggered by certain PRRs can have serious pathological consequences. The Toll-like receptor (TLR) gene family represents a case in point. TLR7, 8, and 9 were originally identified as receptors specific for bacterial and viral RNA and DNA, but more recent in vitro and in vivo studies have now linked these receptors to the detection of host RNA, DNA, and RNA- or DNA-associated proteins. In this context, they likely play a key role in the development of systemic autoimmune diseases.

Severe acute respiratory syndrome (SARS) presented as an atypical pneumonia that progressed to acute respiratory distress syndrome in ∼20% of cases and was associated with a mortality of about 10%. The etiological agent was a novel coronavirus (CoV). Angiotensin-converting enzyme 2 is the functional receptor for SARS-CoV; DC-SIGN and CD209L (L-SIGN) can enhance viral entry. Although the virus infects the lungs, gastrointestinal tract, liver, and kidneys, the disease is limited to the lungs, where diffuse alveolar damage is accompanied by a disproportionately sparse inflammatory infiltrate. Pro-inflammatory cytokines and chemokines, particularly IP-10, IL-8, and MCP-1, are elevated in the lungs and peripheral blood, but there is an unusual lack of an antiviral interferon (IFN) response. The virus is susceptible to exogenous type I IFN but suppresses the induction of IFN. Innate immunity is important for viral clearance in the mouse model. Virus-specific neutralizing antibodies that develop during convalescence prevent reinfection in animal models.

Tyrosyl phosphorylation plays a critical role in multiple signaling pathways regulating innate and acquired immunity. Although tyrosyl phosphorylation is a reversible process, we know much more about the functions of protein-tyrosine kinases (PTKs) than about protein-tyrosine phosphatases (PTPs). Genome sequencing efforts have revealed a large and diverse superfamily of PTPs, which can be subdivided into receptor-like (RPTPs) and nonreceptor (NRPTPs). The role of the RPTP CD45 in immune cell signaling is well known, but those of most other PTPs remain poorly understood. Here, we review the mechanism of action, regulation, and physiological functions of NRPTPs in immune cell signaling. Such an analysis indicates that PTPs are as important as PTKs in regulating the immune system.

Discovery of a large family of Fc receptor-like (FCRL) molecules, homologous to the well-known receptors for the Fc portion of immunoglobulin (FCR), has uncovered an impressive abundance of immunoglobulin superfamily (IgSF) genes in the human 1q21–23 chromosomal region and revealed significant diversity for these genes between humans and mice. The observation that FCRL representatives are members of an ancient multigene family that share a common ancestor with the classical FCR is underscored by their linked genomic locations, gene structure, shared extracellular domain composition, and utilization of common cytoplasmic tyrosine-based signaling elements. In contrast to the conventional FCR, however, FCRL molecules possess diverse extracellular frameworks, autonomous or dual signaling properties, and preferential B lineage expression. Most importantly, there is no strong evidence thus far to support a role for them as Ig-binding receptors. These characteristics, in addition to their identification in malignancies and autoimmune disorders, predict a fundamental role for these receptors as immunomodulatory agents in normal and subverted B lineage cells.

The death domain (DD) superfamily comprising the death domain (DD) subfamily, the death effector domain (DED) subfamily, the caspase recruitment domain (CARD) subfamily, and the pyrin domain (PYD) subfamily is one of the largest domain superfamilies. By mediating homotypic interactions within each domain subfamily, these proteins play important roles in the assembly and activation of apoptotic and inflammatory complexes. In this chapter, we review the molecular complexes assembled by these proteins, the structural and biochemical features of these domains, and the molecular interactions mediated by them. By analyzing the potential molecular basis for the function of these domains, we hope to provide a comprehensive understanding of the function, structure, interaction, and evolution of this important family of domains.

Epstein-Barr virus (EBV) provides a useful model to study cellular immunity to a genetically stable, persistent human virus. Different sets of proteins expressed during EBV's lytic and cell transforming infections induce qualitatively different cellular immune responses. The factors governing immunodominance hierarchies and the biological effectiveness of these different responses are now being revealed. Analysis of infectious mononucleosis (IM), a clinical syndrome that can arise during primary EBV infection, has allowed the evolution of the responses to be tracked over time, giving an understanding of the immune response kinetics and of those determinants affecting selection into memory. Furthermore, following IM, expression of the receptor for the homeostatic cytokine IL-15 on NK and T cells is lost within these individuals. This experiment of nature provides a system to advance understanding of immunological homeostasis in humans, illustrating how data obtained from the study of EBV have wider significance to the immunological community.