Induction Of Anergy Research Articles

Runx1 is a key regulator of T cell anergy

Abstract The transcription factor Runx1 is critical for T cell development and maturation. CD4-Cre Runx1 conditional knockout mice have a block in T cell maturation, leading to complement deposition on recent thymic emigrants, and leaving very few CD4+T cells in peripheral lymphoid organs. Interestingly, thymic- and splenic-derived T cells from CD4-Cre Runx1 cKO mice exhibit increased expression of markers indicative of anergy including FR4 and CD73, which is not seen in other genetically modified mice with a block in T cell maturation. These data suggest Runx1 plays a role in regulating the development of T cell anergy in CD4+T cells. We have generated a 1:1 mixed bone marrow chimera (BMC) system with Estrogen Receptor-Cre (ER-Cre) Runx1 conditional knockout and wild type B6.SJL bone marrow to delete Runx1 in mature CD4+ T cells. Upon tamoxifen treatment and deletion of Runx1, the ER-Cre Runx1 cKO CD4+ T cells spontaneously develop an anergic phenotype as they fail to proliferate upon TCR/CD28 stimulation, and co-express CD73 and FR4. This cell surface phenotype is cell intrinsic since wild type B6.SJL CD4+ T cells in the mixed bone marrow chimera do not upregulate CD73 and FR4 upon tamoxifen treatment. Surprisingly, the mixed BMC system reveals both the ER-Cre Runx1 cKO and the wild type B6.SJL peripheral T cells fail to proliferate in response to TCR/CD28 stimulation, suggesting Runx1 also regulates a cell-extrinsic suppressive mechanism controlling T cell tolerance. This cell-extrinsic induction of anergy requires Runx1-deficient CD4+ T cells, but it is not dependent on Runx1-deficient Tregs. Thus, Runx1 is a key regulator of T cell anergy, and further analysis of this BMC model will serve to uncover the mechanism.

Anergy into T regulatory cells: an integration of metabolic cues and epigenetic changes at the Foxp3 conserved non-coding sequence 2.

Peripheral immune self-tolerance relies on protective mechanisms to control autoreactive T cells that escape deletion in the thymus. Suppression of autoreactive lymphocytes is necessary to avoid autoimmunity and immune cell–mediated damage of healthy tissues. An intriguing relationship has emerged between two mechanisms of peripheral tolerance—induction of anergy and Foxp3 + regulatory T (Treg) cells—and is not yet well understood. A subpopulation of autoreactive anergic CD4 T cells is a precursor of Treg cells. We now hypothesize that phenotypic and mechanistic features of Treg cells can provide insights to understand the mechanisms behind anergy-derived Treg cell differentiation. In this short review, we will highlight several inherent similarities between the anergic state in conventional CD4 T cells as compared with fully differentiated natural Foxp3 + Treg cells and then propose a model whereby modulations in metabolic programming lead to changes in DNA methylation at the Foxp3 locus to allow Foxp3 expression following the reversal of anergy.

Regulation of T-Cell Signaling by Post-Translational Modifications in Autoimmune Disease.

The adaptive immune system involves antigen-specific host defense mechanisms mediated by T and B cells. In particular, CD4+ T cells play a central role in the elimination of pathogens. Immunological tolerance in the thymus regulates T lymphocytes to avoid self-components, including induction of cell death in immature T cells expressing the self-reactive T-cell receptor repertoire. In the periphery, mature T cells are also regulated by tolerance, e.g., via induction of anergy or regulatory T cells. Thus, T cells strictly control intrinsic signal transduction to prevent excessive responses or self-reactions. If the inhibitory effects of T cells on these mechanisms are disrupted, T cells may incorrectly attack self-components, which can lead to autoimmune disease. The functions of T cells are supported by post-translational modifications, particularly phosphorylation, of signaling molecules, the proper regulation of which is controlled by endogenous mechanisms within the T cells themselves. In recent years, molecular targeted agents against kinases have been developed for treatment of autoimmune diseases. In this review, we discuss T-cell signal transduction in autoimmune disease and provide an overview of acetylation-mediated regulation of T-cell signaling pathways.

Inhibition of experimental autoimmune encephalomyelitis by tolerance-promoting DNA vaccination focused to dendritic cells.

In this study we analysed the effects of prophylactic biolistic DNA vaccination with plasmids encoding the encephalitogenic protein myelin oligodendrocyte glycoprotein (MOG) on the severity of a subsequently MOGp35-55-induced EAE and on the underlying immune response. We compared the outcome of vaccination with MOG-encoding plasmids alone or in combination with vectors encoding the regulatory cytokines IL-10 and TGF-ß1, respectively. MOG expression was restricted to skin dendritic cells (DCs) by the use of the DC-specific promoter of the fascin1 gene (pFscn-MOG). For comparison, the strong and ubiquitously active CMV promoter was employed (pCMV-MOG), which allows MOG expression in all transfected cells. Expression of IL-10 and TGF-ß1 was controlled by the CMV promoter to yield maximal synthesis (pCMV-IL10, pCMV-TGFß). Co-application of pFscn-MOG and pCMV-IL10 significantly ameliorated EAE pathology, while vaccination with pCMV-MOG plus pCMV-IL10 did not affect EAE outcome. In contrast, vaccination with either of the two MOG-encoding plasmids in combination with pCMV-TGFß significantly attenuated the clinical EAE symptoms. Mechanistically, we observed diminished infiltration of Th17 and Th1 cells as well as macrophages/DCs into the CNS, which correlated with decreased MOGp35-55-specific production of IL-17 and IFN-ϫ by spleen cells and reduced peptide-specific T cell proliferation. Our findings suggest deletion of or anergy induction in MOG-specific CD4+ T cells by the suppressive vaccination platform employed. MOG expression driven by the DC-specific fascin1 promoter yielded similar inhibitory effects on EAE progression as the ubiquitously active viral CMV promoter, when coapplying pCMV-TGFß. Our finding that pCMV-IL10 promoted tolerogenic effects only, when coapplied with pFscn-MOG, but not pCMV-MOG suggests that IL-10 affected only directly transfected DCs (pFscn-MOG), but not neighbouring DCs that engulfed MOG-containing vesicles derived from transfected keratinocytes (pCMV-MOG). Thus, due to its DC-restricted expression, the fascin1 promoter might be an interesting alternative to ubiquitously expressed promoters for vaccination strategies.

Nur77 Regulates Nondeletional Mechanisms of Tolerance in T Cells.

Negative selection against highly self-reactive thymocytes is critical for preventing autoimmunity. Thymocyte deletion, anergy induction, and agonist selection are all forms of negative selection that can occur following a high-affinity TCR signal. Of Bim and Nur77, two TCR-induced proteins with proapoptotic function, Bim has been shown to be important for clonal deletion in several model systems, whereas Nur77 was often dispensable. However, Nur77 has been reported to influence other aspects of T cell development by mechanisms that may not be related to its proapoptotic function. In this study, we examined the role of Nur77 during thymocyte development in the presence and absence of Bim to separate apoptotic from nonapoptotic functions of Nur77. Polyclonal Bim-/- and Bim-/-Nur77-/- mice exhibited comparable accumulation of high-affinity signaled CD4+CD8+ double-positive thymocytes and CD8+ and CD4+ single-positive thymocytes. However, combined Bim and Nur77 deficiency increased the frequency of thymic Foxp3+ T regulatory cells and Foxp3-FR4hiCD73hi anergic phenotype CD4+ T cells compared with Bim-/- mice, suggesting that Nur77 expression impairs the development of nonconventional tolerance-inducing cell fates. Using the OT-I RIP-mOVA model, we found that Nur77 deficiency did not substantially impact clonal deletion nor did it exacerbate the defect in clonal deletion in the absence of Bim. However, additional loss of Nur77 in the absence of Bim led to diabetes induction, suggesting that Nur77 promotes tolerance in this context. Together, these data reveal novel nondeletional roles for Nur77 that differ between T cell subsets and have implications for self-tolerance.

Multiple tolerance defects contribute to the breach of B cell tolerance in New Zealand Black chromosome 1 congenic mice.

Lupus is characterized by a loss of B cell tolerance leading to autoantibody production. In this study, we explored the mechanisms underlying this loss of tolerance using B6 congenic mice with an interval from New Zealand Black chromosome 1 (denoted c1(96–100)) sufficient for anti-nuclear antibody production. Transgenes for soluble hen egg white lysozyme (sHEL) and anti-HEL immunoglobulin were crossed onto this background and various tolerance mechanisms examined. We found that c1(96–100) mice produced increased levels of IgM and IgG anti-HEL antibodies compared to B6 mice and had higher proportions of germinal center B cells and long-lived plasma cells, suggesting a germinal center-dependent breach of B cell anergy. Consistent with impaired anergy induction, c1(96–100) double transgenic B cells showed enhanced survival and CD86 upregulation. Hematopoietic chimeric sHEL mice with a mixture of B6 and c1(96–100) HEL transgenic B cells recapitulated these results, suggesting the presence of a B cell autonomous defect. Surprisingly, however, there was equivalent recruitment of B6 and c1(96–100) B cells into germinal centers and differentiation to splenic plasmablasts in these mice. In contrast, there were increased proportions of c1(96–100) T follicular helper cells and long-lived plasma cells as compared to their B6 counterparts, suggesting that both B and T cell defects are required to breach germinal center tolerance in this model. This possibility was further supported by experiments showing an enhanced breach of anergy in double transgenic mice with a longer chromosome 1 interval with additional T cell defects.

MicroRNA-150 modulates intracellular Ca2+ levels in na\xefve CD8+ T cells by targeting TMEM20

Regulation of intracellular Ca2+ signaling is a major determinant of CD8+ T cell responsiveness, but the mechanisms underlying this regulation of Ca2+ levels, especially in naïve CD8+ T cells, are not fully defined. Here, we showed that microRNA-150 (miR-150) controls intracellular Ca2+ levels in naïve CD8+ T cells required for activation by suppressing TMEM20, a negative regulator of Ca2+ extrusion. miR-150 deficiency increased TMEM20 expression, which resulted in increased intracellular Ca2+ levels in naïve CD8+ T cells. The subsequent increase in Ca2+ levels induced expression of anergy-inducing genes, such as Cbl-b, Egr2, and p27, through activation of NFAT1, as well as reduced cell proliferation, cytokine production, and the antitumor activity of CD8+ T cells upon antigenic stimulation. The anergy-promoting molecular milieu and function induced by miR-150 deficiency were rescued by reinstatement of miR-150. Additionally, knockdown of TMEM20 in miR-150-deficient naïve CD8+ T cells reduced intracellular Ca2+ levels. Our findings revealed that miR-150 play essential roles in controlling intracellular Ca2+ level and activation in naïve CD8+ T cells, which suggest a mechanism to overcome anergy induction by the regulation of intracellular Ca2+ levels.

Relationship between CD4 Regulatory T Cells and Anergy In Vivo.

Selective suppression of effector CD4+ T cell functions is necessary to prevent immune cell-mediated damage to healthy tissues. This appears especially true during pregnancy or in individuals predisposed to autoimmunity. Foxp3+ regulatory T (Treg) cells and induction of anergy, an acquired state of T cell functional unresponsiveness in Foxp3- cells, have both been implicated as mechanisms to suppress dangerous immune responses to tissue-restricted self-Ags. Anergic CD4+ T cells and Treg cells share a number of phenotypic and mechanistic traits-including the expression of CD73 and folate receptor 4, and the epigenetic modification of Treg cell signature genes-and an interesting relationship between these two subsets has recently emerged. In this review, we will compare and contrast these two subsets, as well as explore the role of anergy in the generation of peripheral Treg cells.

MOLECULAR AND CELLULAR MECHANISMS MEDIATED BY DENDRITIC CELLS INVOLVED IN THE INDUCTION OF TOLERANCE

Autoimmune diseases and complications after transplantation operations are major public health problem, as they often lead to deterioration in the quality of life, reduce work capacity and disability in the population. To date, the induction of antigen-specific tolerance is the promising method of therapy. During this process dendritic cells play important role. In this review current data of tolerogenic dendritic cells characterization, of factors inducing tolerogenic properties in dendritic cells, development of central and peripheral tolerance by dendritic cells, role of tolerogenic dendritic cells in the formation of regulatory B cells, molecular and cellular mechanisms that are involved in the formation of an immunological tolerance depending on tolerogenic dendritic cells were analyzed. Tolerogenic dendritic cells play a key role in maintaining of immune homeostasis by inducing immunological tolerance mechanisms which are associated with the generation of regulatory T cells, induction of anergy or apoptosis of T cells. Formation of tolerogenic properties in dendritic cells is occurred by various factors that regulate the maturation and differentiation of dendritic cells and induce anti-inflammatory agents synthesis of them. Because of their ability to induce natural and peripheral regulatory T cells, dendritic cells contribute to the development of the central and peripheral tolerance in the organism. Analysis of the results of experimental work demonstrates that in addition to induction of regulatory T cells tolerogenic dendritic cells participate in generating of regulatory B cells that play a role in the formation of tolerance and have the ability to affect the population of regulatory T cells. However, the mechanisms that lead to the formation of B cell population by tolerogenic dendritic cells have not been completely established yet. Review of published data showed that the molecular and cellular mechanisms of immunological tolerance induction by tolerogenic dendritic cells and other regulatory cell subpopulations interacting with each other are similar to a large extent. Currently, the role of tolerogenic dendritic cells in maintaining of immune tolerance is determined generally, however, some aspects require further investigation. Subsequent experimental studies will lead to a better understanding of the signaling mechanisms and the realization of immunological functions of tolerogenic dendritic cells, which provide additional information for application approaches development of tolerogenic dendritic cells for the control of autoimmune diseases and transplant complications.

Early growth response 2 and Egr3 are unique regulators in immune system.

The immune system is evolved to defend the body against pathogens and is composed of thousands of complicated and intertwined pathways, which are highly controlled by processes such as transcription and repression of cellular genes. Sometimes the immune system malfunctions and a break down in self-tolerance occurs. This lead to the inability to distinguish between self and non-self and cause attacks on host tissues, a condition also known as autoimmunity, which can result in chronic debilitating diseases. Early growth response genes are family of transcription factors comprising of four members, Egr1, Egr2, Egr3 and Egr4. All of which contain three cyc2-His2 zinc fingers. Initially, Egr2 function was identified in the regulation of peripheral nerve myelination, hindbrain segmentation. Egr3, on the other hand, is highly expressed in muscle spindle development. Egr2 and Egr3 are induced due to the antigen stimulation and this signaling is implemented through the B and T cell receptors in the adaptive immunity. T cell receptor signaling plays a key role in Egr 2 and 3 expressions via their interaction with NFAT molecules. Egr 2 and 3 play a crucial role in regulation of the immune system and their involvement in B and T cell activation, anergy induction and preventing the autoimmune disease has been investigated. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expression of effector and activated T cells.

Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25-LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25-LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25-LAG3+ cells or treatment with a TGF-β3-expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4+CD25-LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4+CD25-LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.

Comprehensive analysis of epigenetically regulated genes in anergic T cells

T cell anergy is one of the important mechanisms for immune tolerance. The results of many studies investigating the mechanism for T cell anergy induction have revealed that the expression of several genes was up-regulated in anergic T cells. It has also been demonstrated that the molecules encoded on those genes played a critical role in anergy induction. However, the mechanism for their up-regulation has not previously been clarified. We examined in this study the changes in gene expression and DNA methylation status caused by anergy induction. Our results demonstrate that the expression of many genes was changed by anergy induction, and that the DNA methylation status of some of these genes was also changed. We show here by a GO analysis that the extent of the change in methylation status caused by anergy induction was distinct between the groups of genes that were categorized.

Tweaking Mesenchymal Stem/Progenitor Cell Immunomodulatory Properties with Viral Vectors Delivering Cytokines.

Mesenchymal Stem Cells (MSCs) can be found in various body sites. Their main role is to differentiate into cartilage, bone, muscle, and fat cells to allow tissue maintenance and repair. During inflammation, MSCs exhibit important immunomodulatory properties that are not constitutive, but require activation, upon which they may exert immunosuppressive functions. MSCs are defined as "sensors of inflammation" since they modulate their ability of interfering with the immune system both in vitro and in vivo upon interaction with different factors. MSCs may influence immune responses through different mechanisms, such as direct cell-to-cell contact, release of soluble factors, and through the induction of anergy and apoptosis. Human MSCs are defined as plastic-adherent cells expressing specific surface molecules. Lack of MHC class II antigens makes them appealing as allogeneic tools for the therapy of both autoimmune diseases and cancer. MSC therapeutic potential could be highly enhanced by the expression of exogenous cytokines provided by transduction with viral vectors. In this review, we attempt to summarize the results of a great number of in vitro and in vivo studies aimed at improving the ability of MSCs as immunomodulators in the therapy of autoimmune, degenerative diseases and cancer. We will also compare results obtained with different vectors to deliver heterologous genes to these cells.

Checkpoints for Autoreactive B Cells in the Peripheral Blood of Lupus Patients Assessed by Flow Cytometry.

Antinuclear antibodies (ANAs) are diagnostic in several autoimmune disorders, yet the failure to achieve B cell tolerance in these diseases is still poorly understood. Although secreted ANAs detected by an indirect immunofluorescence assay are the gold standard for autoreactivity, there has been no convenient assay with which to measure the frequency of circulating B cells that recognize nuclear antigens (ANA+ B cells) in patients. The aim of this study was to generate an assay to easily identify these B cells and to examine its utility in a study of autoreactive B cells in systemic lupus erythematosus (SLE). We developed and validated a novel flow cytometry-based assay that identifies ANA+ B cells using biotinylated nuclear extracts, and utilized it to examine B cell tolerance checkpoints in peripheral blood mononuclear cells obtained from SLE patients and healthy controls. We observed progressive selection against ANA+ B cells as they matured from transitional to naive to CD27+IgD- and CD27+IgD+ memory cells in both healthy subjects and SLE patients; however, ANA+ naive B cells in SLE patients were not anergized to the same extent as in healthy individuals. We also showed that anergy induction is restored in SLE patients treated with belimumab, an inhibitor of BAFF. This assay will enable studies of large populations to identify potential genetic or environmental factors affecting B cell tolerance checkpoints in healthy subjects and patients with autoimmune disease and permit monitoring of the B cell response to therapeutic interventions.

SPECIFIC ALLERGEN IMMUNOTHERAPY RESULTS IN CHILDREN WITH ASTHMA DUE TO POLLENS ALLERGY. CLINICAL STUDY

Introduction. Specific allergen immunotherapy (STI) is the causal treatment of asthma. SIT gives a specific response to the changing LT response (deviation of the immune response), induction of anergy (decrease of LTh2), induces tolerance and modifies the inflammatory response. Pollen produces in our country seasonal allergic asthma in children and adults. Materials and methods. Our study was conducted using grass pollen extracts and comprised a total of 47 children with asthma, allergic to pollens, aged 5-14. Administration was seasonal (November to April), oral (sublingual solutions). It was indicated in the treatment of children with asthma and rhinitis with definite diagnosis where eviction was not possible. There have been previously detailed history and a careful clinical examination, skin prick tests to pollens with intense response, more elevated IgE, and spirometry confirming bronchospasm. Grass pollen extracts with initial low doses were used, gradually increasing the amount and concentration, and a gradual decrease, at a total of 6 months per year, with a duration of three years. Discussion. The evaluation was performed by clinical follow-up (symptom score and drug consumption), spirometry and by improving the quality of life assessment. There were no serious side effects during treatment. Conclusion. SIT in children with pollens allergic asthma is the causal therapeutic method; treating asthmatic children over 3 years old; reduces asthma symptoms to extinction; decreases other medical needs; improves quality of life of the child; no side effect were distinguished.

NFIL3 and Ets1 co-regulate a cluster of genes, including Tim-3, that is associated with T cell tolerance

Abstract Inhibitory receptor Tim-3 has critical roles in the suppression of effector T cell function. Here we demonstrate that the expression of Tim-3 is highly associated with T cell tolerance induction. TCR other than CD28 co-stimulatory signal is required for its induction. This process is accompanied with inhibition of IL-2 but upregulation of IL-10. Among the downstream pathways of TCR signaling, the calcium-calmodulin-dependent Kinase II (CaMKII) pathway is essential for Tim-3, IL-10 induction and IL-2 inhibition. CaMKII directly regulates transcription factors Ets1 and NFIL3. While NFIL3 induces Tim-3, IL-10 and suppresses IL-2 expression, Ets1 plays an opposite role for their expression. Accordingly, functional analyses suggest that NFIL3 is required, but Ets1 actually has an opposite role, in maintaining T cell tolerance/anergy. ChIP-Seq results reveal that NFIL3 and Ets1 co-localize in the loci of Tim-3, IL-2 and IL-10, suggesting a functional cooperation between NFIL3 and Ets1 in the regulation of these genes. We further identified a cluster of genes that has direct binding with both NFIL3 and Ets1. RNA-seq analysis reveals that the expression of these genes is associated with ionomycin-mediated T cell anergy induction. Collectively, our study suggests that NFIL3 and Ets1 cooperatively regulate a transcriptional network to control the expression of a cluster of genes, including Tim-3, IL-10, and IL-2, that is functionally important for T cell tolerance/anergy induction.

IL-17 receptor A signaling impedes NF-κB p50/p50 repressor and subverts B-cell anergy in BXD2 mice

Abstract B-cell fate decision checkpoint 2 at the transitional T2 stage represents a critical checkpoint defect in the development of autoimmune disease. We have found that there is a failure of anergy induction in the CD93+IgM+CD23+ transitional T2 B cells in the spleen of lupus prone BXD2 mice, which is associated with B-cell tolerance loss to anti-IgM or TLR7 in vitro. Interestingly, there was an enhanced BXD2-Il17ra−/− T2 B cell anergy phenotype in vivo, which is associated with a strong B cell anergic response to BCR or TLR7 stimulation in vitro. Abnormal survival of T2 B cells is thought to be regulated through a strong BAFF-R signaling. Surprisingly, despite normal expression of BAFF-R, BlyS cannot reverse the anergic response of BXD2-Il17ra−/− B cells to BCR stimulation. Analysis of the expression of IL-17RA in the B-cell subsets in BXD2 mice shows that only T2 and germinal center (PNA+Fas+) B cells, but not T1, T3 or mature (CD93−) B cells express surface IL-17RA. Single cell analysis of T2 B cells reveals the co-expression of Il17ra with B-cell activation gene, Bclxl. The strong anergic phenotype of BXD2-Il17ra−/− mouse B cells is associated with a dramatically enhanced nuclear expression of NF-κB1 (p50) and down-modulation of NF-κB phospho-p65. Our results suggest that, in BXD2-Il17ra−/− B cells, the anergy phenotype is established at the T2 stage. In these B cells, the stimulus-specific transcription repressor p50/p50 homodimer may act as a master transcriptional regulator to counteract pro-activation/survival NF-κB signaling provided by other major B-cell stimulators to enforce B cell anergy. Reagents that can promote the NF-κB p50/p50 repressome complex may be a novel strategy to enhance B-cell tolerance for autoimmunity.

Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells.

The liver is a tolerogenic organ with exquisite mechanisms of immune regulation that ensure upkeep of local and systemic immune tolerance to self and foreign antigens, but that is also able to mount effective immune responses against pathogens. The immune privilege of liver allografts was recognized first in pigs in spite of major histo-compatibility complex mismatch, and termed the “liver tolerance effect”. Furthermore, liver transplants are spontaneously accepted with only low-dose immunosuppression, and induce tolerance for non-hepatic co-transplanted allografts of the same donor. Although this immunotolerogenic environment is favorable in the setting of organ transplantation, it is detrimental in chronic infectious liver diseases like hepatitis B or C, malaria, schistosomiasis or tumorigenesis, leading to pathogen persistence and weak anti-tumor effects. The liver is a primary site of T-cell activation, but it elicits poor or incomplete activation of T cells, leading to their abortive activation, exhaustion, suppression of their effector function and early death. This is exploited by pathogens and can impair pathogen control and clearance or allow tumor growth. Hepatic priming of T cells is mediated by a number of local conventional and nonconventional antigen-presenting cells (APCs), which promote tolerance by immune deviation, induction of T-cell anergy or apoptosis, and generating and expanding regulatory T cells. This review will focus on the communication between classical and nonclassical APCs and lymphocytes in the liver in tolerance induction and will discuss recent insights into the role of innate lymphocytes in this process.

Regulation of immunity by Taeniids: lessons from animal models and in vitro studies.

Taeniidae is the largest family of the Cyclophyllidea order of parasites despite being composed of just two genera: Taenia spp and Echinococcus spp. These parasites are flatworms with a terrestrial life cycle, having an immature or larval stage called metacestode, which develops into the mature form within the intestine of the primary host after being consumed in raw or poorly cooked meat. Consumed eggs hatch into oncospheres, penetrate the intestinal walls and are transported via the bloodstream to later develop into metacestodes within the muscles and internal organs of secondary and sometimes primary hosts, thereby initiating the cycle again. Larval stages of both Taenia spp and Echinococcus spp are well known to produce tissue-dwelling, long-lasting infections; in this stage, these parasites can reach centimetres (macroparasites) and both genera may cause life-threatening diseases in humans. Establishing such long-term infections requires an exceptional ability to modulate host immunity for long periods of time. In this review, we analyse the immunoregulatory mechanisms induced by these tapeworms and their products, mainly discussing the importance of taeniid strategies to successfully colonize their hosts, such as antigen-presenting cell phenotype manipulation and the consequent induction of T-cell anergy, among others.

CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors.

The role that anergy, an acquired state of T cell functional unresponsiveness, plays in natural peripheral tolerance remains unclear. In this study, we demonstrate that anergy is selectively induced in fetal antigen-specific maternal CD4+ T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4+ T cells, enriched in self antigen-specific T cell receptors, is also observed in healthy hosts. Neuropilin-1 expression in anergic conventional CD4+ T cells is associated with thymic regulatory T cell (Treg cell)-related gene hypomethylation, and this correlates with their capacity to differentiate into Foxp3+ Treg cells that suppress immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity, but it also generates the precursors for peripheral Treg cell differentiation.