Trends in Immunology

A major challenge for immunologists has been the development of vaccines designed to emphasize cellular immune responses. One particularly promising approach is the prime-boost strategy, which has been shown to generate high levels of T-cell memory in animal models. Recently, several papers have highlighted the power of prime-boost strategies in eliciting protective cellular immunity to a variety of pathogens and have demonstrated efficacy in humans. Coupled with recent advances in our understanding of the mechanisms underlying the generation, maintenance and recall of T-cell memory, the field is poised to make tremendous progress. This Review discusses the impact of these recent developments on the future of prime-boost vaccine strategies.

MHC class I molecules generally present peptides of eight to ten amino acids; however, peptides of 11-14 residues can also elicit dominant cytotoxic T lymphocyte responses, sometimes at the expense of overlapping shorter peptides. Although long-bulged epitopes are considered to represent a barrier for T cell receptor recognition, recent structural data reveal how these super-bulged peptides are engaged while simultaneously maintaining MHC restriction. We propose that algorithms widely used to predict class I-binding peptides should now be broadened to include peptides of over ten residues in length.

Occasionally, the discovery of a new molecule sheds light on an entire biological system. A good example is the discovery of the tumor necrosis factor (TNF)-related molecule, B-cell-activating factor belonging to the TNF family (BAFF), known also as BLyS, TALL-1, zTNF4 or THANK. A flurry of papers from several groups, describing results from transgenic and knockout mice, animal models and human studies, has shown that BAFF is a crucial molecule involved in B-cell maturation and the development of autoimmunity. Several recent reports add to this exciting story and illustrate some of the formative stages of B-cell maturation and tolerance.

Of the multiple unique stromal cell types common to solid tumors, tumor-associated macrophages (TAMs) are significant for fostering tumor progression. The protumor properties of TAMs derive from regulation of angiogenic programming, production of soluble mediators that support proliferation, survival and invasion of malignant cells, and direct and indirect suppression of cytotoxic T cell activity. These varied activities are dependent on the polarization state of TAMs that is regulated in part by local concentrations of cytokines and chemokines, as well as varied interactions of TAMs with normal and degraded components of the extracellular matrix. Targeting molecular pathways regulating TAM polarization holds great promise for anticancer therapy.

IL-12p40 is known as a component of the bioactive cytokines interleukin (IL)-12 and IL-23 but it is not widely recognized as having intrinsic functional activity. Recent publications have altered this perception and support an independent role for IL-12p40. IL-12p40 is induced in excess over the other subunits of IL-12 and IL-23 and can exist in a monomeric or homodimeric form. Its most widely appreciated function is to provide a negative feedback loop by competitively binding to the IL-12 receptor. However, IL-12p40 acts as a chemoattractant for macrophages and promotes the migration of bacterially stimulated dendritic cells. It is associated with several pathogenic inflammatory responses such as silicosis, graft rejection and asthma but it is also protective in a mycobacterial model. An appreciation of the independent function of IL-12p40 is important for improving our understanding of both protective and pathogenic immune responses.

Langerhans cells (LCs) are prominent dendritic cells (DCs) in epithelia, but their role in immunity and tolerance is poorly defined. 'Knockin' mice expressing enhanced green fluorescent protein (EGFP) under the control of the langerin (CD207) gene were recently developed in order to discriminate epidermal LCs from other DC subsets and at the same time to track their dynamics under steady-state or inflammatory conditions in vivo. Additional knockin mice expressing a diphtheria toxin receptor fused to EGFP were used to conditionally ablate LCs and assess their role in triggering hapten-specific T cell effectors through skin immunization. We review the insights that have been provided by these various knockin mice and discuss gaps in our knowledge of LCs that need to be filled.

CD69 is an early leukocyte activation molecule expressed at sites of chronic inflammation. The precise role of CD69 in immunity has not been elucidated owing to the absence of a known ligand and adequate in vivo models to study its physiological function. Although previous in vitro studies suggest that CD69 is an activatory molecule in different leukocyte subsets, recent studies in CD69-deficient mice have revealed a non-redundant role for this receptor in downregulation of the immune response through the production of the pleiotropic cytokine transforming growth factor-β (TGF-β). The possible cellular and molecular mechanisms of action of this molecule are discussed herein.

Innate immunity is a constitutive component of the central nervous system (CNS) and relies strongly on resident myeloid cells, the microglia. However, evidence is emerging that the most abundant glial cell population of the CNS, the astrocyte, participates in the local innate immune response triggered by a variety of insults. Astrocytes display an array of receptors involved in innate immunity, including Toll-like receptors, nucleotide-binding oligomerization domains, double-stranded RNA-dependent protein kinase, scavenger receptors, mannose receptor and components of the complement system. Following activation, astrocytes are endowed with the ability to secrete soluble mediators, such as CXCL10, CCL2, interleukin-6 and BAFF, which have an impact on both innate and adaptive immune responses. The role of astrocytes in inflammation and tissue repair is elaborated by recent in vivo studies employing cell-type specific gene targeting.

The hygiene hypothesis proposes that several chronic inflammatory disorders (allergies, autoimmunity, inflammatory bowel disease) are increasing in prevalence in developed countries because a changing microbial environment has perturbed immunoregulatory circuits which normally terminate inflammatory responses. Some stress-related psychiatric disorders, particularly depression and anxiety, are associated with markers of ongoing inflammation, even without any accompanying inflammatory disorder. Moreover, pro-inflammatory cytokines can induce depression, which is commonly seen in patients treated with interleukin-2 or interferon-alpha. Therefore, some psychiatric disorders in developed countries might be attributable to failure of immunoregulatory circuits to terminate ongoing inflammatory responses. This is discussed in relation to the effects of the immune system on a specific group of brain serotonergic neurons involved in the pathophysiology of mood disorders.

Allergy is a complex inflammatory disease, the etiology of which is well defined. It has recently been proposed that eosinophil, mast-cell and fibroblast interactions contribute to allergy perpetuation. Moreover, mast-cell-derived tryptase might act as a link among these cells. This hypothesis is supported by two recent papers that show that tryptase, seemingly through the protease-activated receptor-2, mediates eosinophil infiltration in the airways and fibroblast proliferation that depends on both cyclooxygenase and prostaglandin synthesis.

With the identification of T helper (Th)17 cells, a specific subset of CD4 T cells expressing interleukin (IL)-17 and IL-22, research on the function of these cytokines initially largely focused on traditional adaptive immune responses. However, IL-17 and IL-22 enhance basic innate barrier defenses at mucosal surfaces, such as antimicrobial peptide production and neutrophil recruitment; both events that occur rapidly and precede adaptive phase immunity. At the intestinal mucosal surface, it is now clear that innate lymphoid cells are also important sources of IL-17 and IL-22 during early phases of infection. Here, we discuss the function of innate IL-17- and IL-22-producing lymphocytes during enteric bacterial infection and their regulation by the intestinal microbiota, Toll-like receptors (TLRs) and Nod-like receptors (NLRs).

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is widely used to dissect molecular mechanisms of MS and to develop new therapeutic strategies. The T helper 17 (Th17) subset of CD4 T cells plays a crucial role in the development of EAE. IL-17, a cytokine produced by Th17 cells, participates in EAE pathogenesis through induction of inflammatory gene expression in target cells. Recent work has shown that Act1, a U-box E3 ubiquitin ligase, is recruited to IL-17 receptor (IL-17R) upon IL-17 stimulation and is required for IL-17-mediated signaling. Here, we review the molecular and cellular mechanisms by which IL-17 and Act1-mediated signaling contribute to EAE.

T helper (Th) 17 cells represent a third effector arm of CD4 T cells and complement the function of the Th1 and Th2 cell lineages. Here, we provide an overview of the transcription factors, cytokines, chemokines, and cytokine and chemokine receptors that characterize the Th17 cell phenotype. Data relevant for human Th17 cells are emphasized, with a focus on the function of two markers that have recently been associated with human Th17 cells, CD161 and interleukin-4-induced gene 1 (IL4I1). Also considered is the basis of Th17 cell plasticity towards the Th1 lineage, and we suggest that this plasticity together with the limited expansion of Th17 cells in response to T cell receptor (TCR) triggering accounts for the rarity of human Th17 cells in inflamed tissues.

γδ T cells are the major initial interleukin (IL)-17 producers in acute infections. Recent studies have indicated that some γδ T cells have IL-17-producing capabilities without explicit induction of an immune response. They are preferentially localized in barrier tissues and are likely to originate from fetal γδ thymocytes. In addition, γδ T cells present in the secondary lymphoid organs will mature and differentiate to produce IL-17 after antigen encounter in an immune response. Based on these studies, we propose that there are two different sets of IL-17-producing γδ T cells (Tγδ17) referred to as the 'natural' and the 'inducible' Tγδ17 cells. This review focuses on recent publications leading to the delineation of these two types of cells and their implied roles in host immune defense.

Cutaneous and mucosal epithelial cells function as both a physical barrier and as immune sentinels against environmental challenges, such as microbial pathogens, allergens and stress. The crosstalk between epithelial cells and leukocytes is essential for orchestrating proper immune responses during host defense. Interleukin (IL)-17 family cytokines are important players in regulating innate epithelial immune responses. Although IL-17A and IL-17F promote antibacterial and antifungal responses, IL-17E is essential for defense against parasitic infections. Emerging data indicate that another member of this family, IL-17C, specifically regulates epithelial immunity. IL-17C production serves as an immediate defense mechanism by epithelial cells, utilizing an autocrine mechanism to promote antibacterial responses at barrier surfaces.

T helper (Th)17 cells have been proposed to represent a new CD4(+) T cell lineage that is important for host defense against fungi and extracellular bacteria, and the development of autoimmune diseases. Precisely how these cells arise has been the subject of some debate, with apparent species-specific differences in mice and humans. Here, we describe evolving views of Th17 specification, highlighting the contribution of transforming growth factor-β and the opposing roles of signal transducer and activator of transcription (STAT)3 and STAT5. Increasing evidence points to heterogeneity and inherent phenotypic instability in this subset. Ideally, better understanding of expression and action of key transcription factors and the epigenetic landscape of Th17 can help explain the flexibility and diversity of interleukin-17-producing cells.

Transforming growth factor (TGF)beta is most commonly considered an anti-inflammatory cytokine, a view that clearly does not correlate with the recently described role for TGFbeta1 in the differentiation of T-helper (Th)17 cells, a novel, highly inflammatory T-cell subset that produces interleukin (IL)-17. However, these recent findings endorse earlier studies, pre-dating the discovery of Th17 cells, which described a seemingly paradoxical pro-inflammatory role of TGFbeta. In this article, we propose that the administration of neutralizing anti-TGFbeta antibodies in target sites of chronic inflammation would ameliorate or abolish disease because this would limit the differentiation of Th17 cells. By contrast, similar interventions at mucosal sites, where Th17 cells seem to have a protective role, might exacerbate disease in experimental models of colitis. An excess production of Th17 cells in response to infection or trauma could result in leakage into peripheral tissues and cause autoimmune pathology.

T helper (Th) cell subsets secrete cytokines that regulate other immune cells. Interleukin (IL)-17 and IL-22 belong to a new class of cytokines with predominant effects on epithelial cells. Thus, these cytokines are key molecules in several disease processes. IL-17 and IL-22 are released by leukocytes such as Th and natural killer cell populations. Both IL-17 and IL-22 induce an innate immune response in epithelial cells, but their functional spectra are generally distinct. IL-17 induces an inflammatory tissue response and is involved in the pathogenesis of several autoimmune diseases, whereas IL-22 is protective/regenerative. This review juxtaposes IL-17 and IL-22 and describes overlaps and differences regarding their cellular sources, biochemical structure, signaling cascades in target cells, and function.

Interleukin (IL)-23 is a heterodimeric cytokine closely related to IL-12. Yet, despite a strong structural relationship that includes a shared p40 subunit, this does not translate into functional similarity. In fact, the opposite is true, in that these two cytokines appear to have profoundly different roles in regulating host immune responses. It is now clear that IL-23 has key roles in autoimmune destruction in experimental allergic encephalomyelitis, collagen-induced arthritis and inflammatory bowel disease. IL-23 drives the development of autoreactive IL-17-producing T cells and promotes chronic inflammation dominated by IL-17, IL-6, IL-8 and tumor necrosis factor as well as neutrophils and monocytes. It is unlikely that IL-23 and its downstream effects evolved just to cause autoimmunity, but its real benefit to the host and the lineage relationship between IL-17-producing cells and T helper 1 cells remain unclear. By comparing the pathophysiological function of IL-12 and IL-23 in the context of host defense and autoimmune inflammation, we are beginning to understand the novel IL-23-IL-17 immune pathway.

Specific immunotherapy (SIT) is a common treatment for allergic diseases. Despite its usage in clinical practice for nearly a century, more-rational and safer allergen preparations are required. Here, the underlying mechanisms and principles of allergen modification for the future use of SIT in the treatment of allergy are discussed.

Interleukin-1β (IL-1β) and IL-18 contribute to host defense against infection by augmenting antimicrobial properties of phagocytes and initiating Th1 and Th17 adaptive immune responses. Protein complexes called inflammasomes activate intracellular caspase-1 autocatalytically, which cleaves the inactive precursors of IL-1β and IL-18 into bioactive cytokines. In this review, we discuss the controversies regarding inflammasome activation and the role of the inflammasome during infection. We highlight alternative mechanisms for processing IL-1β and IL-18 during infection, which involve extracellular cleavage of the inactive cytokines by neutrophil-derived serine proteases or proteases released from cytotoxic T cells.

Infectious diseases, including tuberculosis, malaria, hepatitis, pneumonia, dysentery, and helminth infestations, still constitute a profound threat in developing countries. Curiously, their decline in high-income societies is paralleled by an unprecedented emergence of allergic disorders, notably asthma and atopy, and chronic inflammatory and autoimmune diseases, such as Crohn's disease, type 1 diabetes, and multiple sclerosis. Several changes in lifestyle are associated with this transition, including diminished exposure to soil and animals, nutritional bias, obesity and increased exposure to pollutants and antibiotics, which all impact the intestinal microbiota. Understanding the mechanistic links behind the epidemiological observations, the complexity of a changing microbiome, and the immunoregulatory consequences of microbial encounter in barrier organs was the subject of the 99(th) Dahlem Conference.

The transmembrane CD83 molecule, a conserved member of the immunoglobulin superfamily, is known as one of the most characteristic cell surface markers for fully matured dendritic cells (DCs) in the peripheral circulation. An essential role for CD83 on murine DCs has not been found; however, evidence shows that its function primarily lies in the regulation of T- and B-lymphocyte maturation and in the regulation of their peripheral responses. Here, we review evidence for a role of CD83 in central lymphocyte maturation and novel, sometimes contradictory findings, regarding the function of CD83 in peripheral immune responses.

Mitogen-activated protein kinases (MAPKs), including p38 and c-Jun N-terminal kinase (JNK), have a key role in T cell receptor (TCR)-induced gene transcription but their precise mechanism of activation is not well understood. The findings of two recent papers provide new insight into the activation of p38 and JNK by the membrane-associated guanylate kinase (MAGUK) family members Dlgh1 and Carma1, respectively, and show how distinct MAGUK proteins control specific aspects of TCR-mediated MAPK activation.