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• The immune cell repertoire is controlled through T cell receptor and costimulatory molecule dependant selection of CD4+ and Foxp3+ T cells in the thymus. • The immune response to antigen is fine-tuned through activation induced cell death. • Chronic exposure to antigen leads to desensitization of immune responses through anergy and the generation of regulatory type 1 responses. • Differentiation of anergic Tr1 cells arises from radically reduced cell signalling and epigenetic priming of tolerance associated genes. • Autoimmune responses are successfully controlled by chronic exposure to antigen processing independent T cell epitopes. Lymphocyte receptors confer antigen specificity on the adaptive immune response. Increasing evidence points to the role of adaptive tuning particularly amongst CD4+ T cell responses. This review summarises how T cell tuning impacts on critically important aspects of immune regulation including thymic selection, the immune response to chronic antigen exposure and antigen-specific immunotherapy of autoimmune conditions. Recent work has revealed a novel mechanism for T cell anergy and regulatory type 1 T cell differentiation through a limitation of T cell receptor mediated signalling combined with epigenetic priming of tolerance associated genes. [ABSTRACT FROM AUTHOR]

• Specific immunotherapy is the 'holy grail' for treatment of autoimmunity. • Antigens are delivered by either direct or indirect presentation mechanisms. • Liver APC and steady state DC mediate distinct forms of immune regulation. • Tr1 cell induction involves epigenetic modification of tolerance associated genes. • Trials reveal that antigen-specific immunotherapy can control autoimmune diseases. Current treatments for autoimmune diseases do not address the immune pathology underlying their initiation and progression and too often rely on non-specific immunosuppressive drugs for control of symptoms. Antigen-specific immunotherapy aims to induce tolerance selectively among the cells causing the disease while leaving the rest of the adaptive immune system capable of protecting against infectious diseases and cancers. Here we describe how novel approaches for antigen-specific immunotherapy are designed to manipulate antigen presentation and promote tolerance to specific self-antigens. This analysis points to liver antigen presenting cells, targeted by carrier particles, and steady-state dendritic cells, to which antigen-processing independent T-cell epitopes (apitopes) bind directly, as the principal targets for antigen-specific immunotherapy. Delivery of antigens to these cells holds great promise for effective control of this rapidly expanding group of diseases. [ABSTRACT FROM AUTHOR]

Antigen-specific immunotherapy is considered the holy-grail for treatment of autoimmune diseases. However, unlike the unattainable myth of Arthurian legend, effective antigen-specific immunotherapy is now being realised through clinical trials in patients. This review describes the various approaches being taken, how antigens are being designed for therapy and carriers created for their delivery. A critical assessment is made concerning the need for such carrier systems. [ABSTRACT FROM AUTHOR]

Adoptive transfer of antigen-specific, in vitro-induced Foxp3 + Treg (iTreg) cells protects against autoimmune disease. To generate antigen-specific iTreg cells at high purity, however, remains a challenge. Whereas polyclonal T cell stimulation with anti-CD3 and anti-CD28 antibody yields Foxp3 + iTreg cells at a purity of 90–95%, antigen-induced iTreg cells typically do not exceed a purity of 65–75%, even in a TCR-transgenic model. In a similar vein to thymic Treg cell selection, iTreg cell differentiation is influenced not only by antigen recognition and the availability of TGF-β but also by co-factors including costimulation and adhesion molecules. In this study, we demonstrate that blockade of the T cell integrin Leukocyte Function-associated Antigen-1 (LFA-1) during antigen-mediated iTreg cell differentiation augments Foxp3 induction, leading to approximately 90% purity of Foxp3 + iTreg cells. This increased efficacy not only boosts the yield of Foxp3 + iTreg cells, it also reduces contamination with activated effector T cells, thus improving the safety of adoptive transfer immunotherapy. [ABSTRACT FROM AUTHOR]

Approximately 1 in 20 individuals in Europe and North America suffers from an autoimmune disease. Current treatments are nonspecific and fail to prevent the underlying autoimmune response. Regulatory T cells have been shown to control autoimmunity in healthy individuals. Here we focus on strategies developed to promote immune regulation through the administration of antigenic peptides. [Copyright &y& Elsevier]

The immune system is a delicately balanced network of interacting cells. In recent years, the concept of immune regulation/suppression has been firmly established, and both natural and induced regulatory cells play vital roles in protection from autoimmune disease. Recent work has revealed the diverse nature of regulatory CD4+ T (Treg) cells and the molecules involved in their function. Innate and adaptive responses to infection are able to override the suppressive properties of such regulatory cells, whereas several reports point to deficiencies in regulatory cell function in autoimmune disease. Protocols have been developed that allow the expansion of Treg cells in vitro and their antigen-specific induction in vivo. A full understanding of Treg differentiation and function will facilitate the development of improved strategies for prevention and treatment of autoimmune diseases. [Copyright &y& Elsevier]

T-cells provide antigen specific focus to the adaptive immune response. However, the receptors that initiate functional responses are not in themselves specific, as they can recognise many different ligands. In this paper, we propose that the immune system deals with TCR degeneracy by an adaptive process that effects both T-cell activation and T-cell function, and exploits TCR degeneracy to limit pathogenic autoimmune disease. [Copyright &y& Elsevier]

Abstract: Recent advances in immunology have led to exciting new possibilities in medicine. We now understand how to design vaccine capable of resetting the balance between immune effector and regulatory cells in people suffering from autoimmune and allergic diseases. These approaches are effective while avoiding the side effects associated with non-specific immune suppression. [Copyright &y& Elsevier]

Immunological homeostasis in T cells is maintained by a tightly regulated signaling and transcriptional network. Full engagement of effector T cells occurs only when signaling exceeds a critical threshold that enables induction of immune response genes carrying an epigenetic memory of prior activation. Here we investigate the underlying mechanisms causing the suppression of normal immune responses when T cells are rendered anergic by tolerance induction. By performing an integrated analysis of signaling, epigenetic modifications, and gene expression, we demonstrate that immunological tolerance is established when both signaling to and chromatin priming of immune response genes are weakened. In parallel, chromatin priming of immune-repressive genes becomes boosted, rendering them sensitive to low levels of signaling below the threshold needed to activate immune response genes. Our study reveals how repeated exposure to antigens causes an altered epigenetic state leading to T cell anergy and tolerance, representing a basis for treating auto-immune diseases. • Activation of immune response genes is suppressed in tolerant T cells • Epigenetic priming of repressive genes is boosted when tolerance is established • Inhibitory receptor genes have a lower threshold of activation in tolerant cells • Induction of tolerance by peptides points toward a therapy for multiple sclerosis Autoimmune diseases such as multiple sclerosis (MS) are caused by T cells reacting to host proteins. Bevington et al. use escalating doses of a MS auto-antigen to induce tolerance in T cells in mice, and define a mechanism whereby antigen activates repressive genes while silencing immune response genes. [ABSTRACT FROM AUTHOR]

Nearly a century has passed since the first report describing antigen-specific immunotherapy (antigen-SIT) was published. Research into the use of antigen-SIT in the treatment of both allergic and autoimmune disease has increased dramatically since, although its mechanism of action is only slowly being unravelled. It is clear though, from recent studies, that success of antigen-SIT depends on the induction of regulatory T (T reg) cell subsets that recognise potentially disease-inducing epitopes. The major challenge remaining for the widespread use of antigen-SIT is to safely administer high doses of immunodominant and potentially pathogenic epitopes in a manner that induces T cell tolerance rather than activation. This review illustrates that intelligent design of treatment agents and strategies can lead to the development of safe and effective antigen-SIT. [ABSTRACT FROM AUTHOR]

CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) have a profound ability to control immune responses. We have previously shown that the liver is a major source of peripherally induced Tregs. Here, we investigate the liver cell types and molecular mechanisms responsible for hepatic Treg induction. Methods To assess the Treg-inducing potential of liver resident antigen-presenting cell types, we studied the conversion of Foxp3− non-Tregs into Foxp3+ Tregs induced by liver dendritic cells (DCs), liver sinusoidal endothelial cells (LSECs), or Kupffer cells (KCs). The dependency of Treg induction on TGF-β was tested in Treg conversion assays using T cells with reduced TGF-β sensitivity. The suppressive potential of liver cell-induced Tregs was assessed by an in vitro suppression assay and in vivo, in the model of experimental autoimmune encephalomyelitis (EAE). Results All tested liver cell types were capable of inducing Foxp3+ Tregs; however, LSECs were most efficient in inducing Tregs. Treg-induction was antigen-specific and depended on TGF-β. LSECs featured membrane-bound LAP/TGF-β and the anchor molecule GARP, which is required for tethering LAP/TGF-β to the cell membrane. LSEC-induced Tregs suppressed proliferation and cytokine secretion of effector T cells in vitro. LSEC-induced Tregs were also functional suppressors in vivo, as neuroantigen-specific Tregs induced by LSECs were able to suppress EAE. Conclusions We demonstrate that LSECs are the major liver cell type responsible for TGF-β dependent hepatic Treg induction. The extraordinary capacity of LSECs to induce Tregs was associated with their unique ability to tether TGF-β to their membrane. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have expanded our understanding of the role of the anti-inflammatory cytokine interleukin (IL)–10, produced by multiple lineages of both human and murine T cells, in regulating the immune response. Here, we demonstrate that the small percentage of circulating CD4+ T cells that secrete IL-10 can be isolated from human peripheral blood and, importantly, we have optimized a protocol to expand these cells in both antigen-specific and polyclonal manners. Expanded CD4+IL-10+ T cells abrogate proliferation and T helper (Th) 1–like cytokine production in an antigen-specific manner, and to a lesser extent exhibit bystander suppressive capacity. CD4+IL-10+ T cells are suppressive in a cell contact–dependent way, though they do not require secretion of IL-10 for their suppressive role in vitro. CD4+IL-10+ T cells have an activated phenotype, with high expression of CD25, CD69, and cytotoxic T-lymphocyte antigen-4, and are largely FoxP3 negative. This novel method for the isolation and expansion of suppressive IL-10–secreting T cells has important implications both for further research and clinical therapeutic development. [Copyright &y& Elsevier]

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease commonly employed as a model for multiple sclerosis. Extensive studies have demonstrated that EAE may be prevented or ameliorated by the intranasal administration of soluble peptides representing encephalitogenic epitopes. There is increasing evidence that this peptide administration may function via the generation of regulatory cells. The mechanism of action of these cells remains controversial and it seems likely that it may vary between experimental models. At present the majority of work on regulatory cells has centred on characterising naturally occurring regulators, or those generated artificially ex vivo, and less is known about induced regulatory cells produced following peptide administration. This report aims to briefly outline the evidence for the existence of natural regulatory T cells and to introduce the sub-types of induced regulatory T cells now recognised.In several of these regulatory cell systems investigated to date, interleukin-10 (IL-10) has been shown to be important in cell function. This has not been directly investigated in a model employing peptide therapy to induce peripheral tolerance, hence the purpose of this study was to investigate the role of IL-10 in the generation of these regulatory cells. This work has employed both a TCR transgenic mouse system, for predominantly in vitro studies of cell function, and an IL-10 knock-out mouse strain to investigate in vivo disease protection. The results summarised in this report demonstrate that IL-10 is fundamentally important in the generation of disease protection following intranasal peptide therapy. [Copyright &y& Elsevier]