Induction Of Central Tolerance Research Articles

CCR4 is required for efficient thymocyte medullary entry and central tolerance induction (HEM7P.230)

Abstract Clonal deletion of auto-reactive thymocytes is essential for the establishment of central tolerance. The thymic medulla is a specialized microenvironment in which post-positive selection thymocytes are screened for reactivity against a wide range of self-antigens. Autoreactive cells are tolerized via clonal deletion or differentiation into the regulatory T cell lineage. Both thymic dendritic cells (DCs) and medullary thymic epithelial cells (mTECs) present auto-antigens to thymocytes to induce central tolerance. Thus, it is critical that post-positive selection thymocytes enter the medulla and interact efficiently with antigen-presenting cells therein to avoid export of autoreactive naïve T cells. We previously demonstrated that although CCR7 is required for medullary accumulation of thymocytes, additional GPCRs must be involved in medullary entry. Here we report that CCR4 is expressed by post-positive selection thymocytes, while CCR4 ligands are expressed by thymic DCs. Using two-photon time-lapse microscopy, we find that CCR4 is required for accumulation of post-positive selection thymocytes in the medulla, as well as efficient interactions between thymocytes and medullary DCs. In the absence of CCR4, thymocytes fail to undergo clonal deletion to low avidity antigens, autoreactive naïve T cells accumulate in secondary lymphoid organs, and autoimmunity ensues. Taken together, these data demonstrate an essential role for CCR4 in the establishment of thymic central tolerance.

Construction of a functional thymic microenvironment from pluripotent stem cells for the induction of central tolerance.

The thymus is required for generation of a self-tolerant, self-restricted T-cell repertoire. The capacity to manipulate or replace thymus function therapeutically would be beneficial in a variety of clinical settings, including for improving recovery following bone marrow transplantation, restoring immune system function in the elderly and promoting tolerance to transplanted organs or cells. An attractive strategy would be transplantation of thymus organoids generated from cells produced in vitro, for instance from pluripotent stem cells. Here, we review recent progress toward this goal, focusing on advances in directing differentiation of pluripotent stem cells to thymic epithelial cells, a key cell type of the thymic stroma, and related direct reprogramming strategies.

Taming the lion: the challenge of immunity in regenerative medicine.

Taming the lion: the challenge of immunity in regenerative medicine.

The contribution of NF-κB signalling to immune regulation and tolerance.

Immune regulation is necessary to control inflammatory responses and to prevent autoimmune diseases. Therefore, mechanisms of central and peripheral tolerance have evolved to ensure that T cells recognize antigens as self- or non-self-antigens. The thymus is crucially important for central tolerance induction to self-antigens via negative selection of T cells. However, if T cells escape negative selection in the thymus and enter the periphery, peripheral mechanisms are active to warrant immune tolerance. Secondary lymphoid organs, as well as tolerogenic dendritic cells and regulatory T cells, play an important role in peripheral tolerance. In chronic inflammatory diseases, tertiary lymphoid organs are sometimes formed that may also be involved in the induction of peripheral tolerance. This review discusses the main processes that are involved in immune regulation and tolerance, and focuses on the contribution of NF-κB signalling to these processes. This narrative review is based on peer-reviewed publications listed on PubMed up to December 2014. The focus of our literature search was on studies investigating the role of (non)canonical NF-κB signalling in central and peripheral mechanisms of tolerance. Only studies published in English language were considered. This review discusses the immune phenotype of mutant mice with defective (non)canonical NF-κB signalling, corroborated with human data, and emphasizes the contribution of the noncanonical NF-κB pathway to immune regulation and tolerance induction. Noncanonical NF-κB signalling has an important immunoregulatory role in the immune system and contributes to both central and peripheral mechanisms of tolerance.

Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD

AbstractDuring acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that mature medullary thymic epithelial cells (mTEChigh) expressing the autoimmune regulator are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEChigh cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4+ T cells during acute GVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEChigh cells. Our data, therefore, indicate that a functional compromise of the medullary mTEChigh compartment may link alloimmunity to the development of autoimmunity during chronic GVHD.

Promiscuous Gene Expression in the Thymus: A Matter of Epigenetics, miRNA, and More?

The induction of central tolerance in the course of T cell development crucially depends on promiscuous gene expression (pGE) in medullary thymic epithelial cells (mTECs). mTECs express a genome-wide variety of tissue-restricted antigens (TRAs), preventing the escape of autoreactive T cells to the periphery, and the development of severe autoimmunity. Most of our knowledge of how pGE is controlled comes from studies on the autoimmune regulator (Aire). Aire activates the expression of a large subset of TRAs by interacting with the general transcriptional machinery and promoting transcript elongation. However, further factors regulating Aire-independent TRAs must be at play. Recent studies demonstrated that pGE in general and the function of Aire in particular are controlled by epigenetic and post-transcriptional mechanisms. This mini-review summarizes current knowledge of the regulation of pGE by miRNA and epigenetic regulatory mechanisms such as DNA methylation, histone modifications, and chromosomal topology.

Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction.

It is unclear why selective deficiency in secreted (s)IgM causes Ab-mediated autoimmunity. We demonstrate that sIgM is required for normal B cell development and selection. The CD5(+) B cells that were previously shown to accumulate in body cavities of sIgM(-/-) mice are not B-1a cells, but CD19(int), CD43(-), short-lived, BCR signaling-unresponsive anergic B-2 cells. Body cavity B-1 cells were >10-fold reduced, including VH11(+) and phosphotidylcholine-specific B-1a cells, whereas splenic B-1 cells were unaffected and marginal zone B cells increased. Follicular B cells had higher turnover rates, survived poorly after adoptive transfer, and were unresponsiveness to BCR stimulation in vitro. sIgM bound to B cell precursors and provided a positive signal to overcome a block at the pro/pre-B stage and during IgVH repertoire selection. Polyclonal IgM rescued B cell development and returned autoantibody levels to near normal. Thus, natural IgM deficiency causes primary autoimmune disease by altering B cell development, selection, and central tolerance induction.

The potential role for regulatory T-cell therapy in vascularized composite allograft transplantation.

Vascularized composite allograft (VCA) transplantation restores defects to a degree not possible by conventional techniques. However, it is limited by the need for long-term immunosuppression and high rates of acute rejection directed against skin. There is therefore a need for a therapy that may shift the risk-benefit ratio in favour of VCA transplantation. Regulatory T cells (Tregs) are a subset of T cells with potent immunoregulatory properties and the potential to promote immunosuppression-free allograft survival. In this review, we consider the evidence for Treg therapy in VCA transplantation. CD4 Tregs are the best-studied immunoregulatory cell type, and a large amount of experimental and clinical data is emerging to endorse their use in VCA transplantation. Data from animal and humanized models are particularly encouraging and demonstrate the potent efficacy of Treg at preventing skin allograft rejection. Moreover, central tolerance induction techniques in VCA transplantation models are demonstrating a dependence on Tregs for graft survival. An improvement in outcomes after VCA transplantation has the potential to revolutionize the field. Several effective therapeutic strategies have demonstrated great promise experimentally, and there is now a need to assess their safety and efficacy in a clinical setting.

P134: ROLE OF AIRE GENE (AUTOIMMUNE REGULATOR) IN TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL REGULATION OF HLA-G

Non-classical HLA-G and HLA-E molecules have well-recognized immunomodulatory effects on peripheral blood immune-competent cells; however, little is known regarding the effect of these molecules in central tolerance. Aire is responsible for promiscuous gene expression of tissue-related antigens by thymic cells during induction of central tolerance. We characterized the differential transcript profiles of murine MHC class Ib (Qa-1/HLA-E, Qa-2/HLA-G) and Aire genes during ontogeny of thymus, and identified that the transcriptional profile of the functional homolog of HLA-G, (H2-Q7/Qa2) was positively correlated with Aire during thymus fetal development, indicating that non-classical MHC class I genes could be under the transcriptional control of Aire. This study aimed to evaluate the transcriptional and post-transcriptional relation between Aire and HLA-G. Using previously validated Aire plasmid-based constructs, we transfected different cell-lines: HLA-G + Cells (JEG3), HLA-G- Cells (U251) and thymic cells (4D6 and LT-TEC2), and assessed HLA-G gene and protein expression. Using an in silico approach, we found 4 putative binding sites for Aire-complex at the 5’-promoter region of the HLA-G gene. We cloned, selected (enzyme digestion: EcoRI/HindIII) and validated (sequencing/alignment) the bacterial-vectors containing Aire. Initially, we observed that only JEG-3 cells were HLA-G + with transcript levels being 10.000-fold greater than the other cell lines and 50% of cell population presenting HLA-G in cell surface. After transient transfection, HLA-G transcript levels were increased only in 4D6 and LT-TEC2 cells (P = 0.03 and P = 0.007, respectively) compared to control (empty-vector). We did not observe any modification in the HLA-G cell surface expression in all cell lines. Concluding, Aire may play a role in the transcriptional regulation of HLA-G, which appears to be cell type-dependent, i. e., primarily inducted in thymic cell lines.

Deciphering the unusual HLA-A2/Melan-A/MART-1-specific TCR repertoire in humans.

The Melan-A/MART-1(26-35) antigenic peptide is one of the best studied human tumor-associated antigens. It is expressed in healthy melanocytes and malignant melanoma and is recognized by CD8(+) T cells in the context of the MHC class I molecule HLA-A*0201. While an unusually large repertoire of CD8(+) T cells specific for this antigen has been documented, the reasons for its generation have remained elusive. In this issue of the European Journal of Immunology, Pinto et al. [Eur. J. Immunol. 2014. 44: 2811-2821] uncover one important mechanism by comparing the thymic expression of the Melan-A gene to that in the melanocyte lineage. This study shows that medullary thymic epithelial cells (mTECs) dominantly express a truncated Melan-A transcript, the product of misinitiation of transcription. Consequently, the protein product in mTECs lacks the immunodominant epitope spanning residues 26-35, thus precluding central tolerance to this antigen. In contrast, melanocytes and melanoma tumor cells express almost exclusively the full-length Melan-A transcript, thus providing the target antigen for efficient recognition by HLA-A2-restricted CD8(+) T cells. The frequency of these alternative gene transcription modes may be more common than previously appreciated and may represent an important factor modulating the efficiency of central tolerance induction in the thymus.

Guest editorial: immunotherapy for hematological malignancies: the quest to overcome tolerogenic drive

How easily a healthy body can defend itself against ordinary pathogens! If only it was possible to do the same against self-derived malignancies. Unfortunately, however, the physiology of the immune system discourages such a persistent fight by establishing the overwhelming hurdle of ‘‘tolerance’’. For this reason, tumor immunotherapy stands as an ultimate challenge to the fundamental basis of immunology. Will we ever win this battle? Recent remarkable advances in related fields are finally beginning to make tumor immunologists confident enough to answer in the affirmative. In fact, it has been hematologists who have led the field of tumor immunotherapy through their work in allogeneic hematopoietic stem cell transplantation, which exploits the power of graft-versus-tumor effects. However, this is inevitably accompanied by graft-versus-host disease, which precludes elderly patients, who represent a major population suffering from hematological malignancies, from receiving allogeneic transplantation. Clearly, we must develop novel therapies for such patients. In contrast to the tremendous power of allogeneic reaction, autologous antitumor responses are usually feeble. Heightening them to a clinically meaningful level is a daunting task in the face of the driving force of tolerance. However, rational strategies for overcoming each step in the series of tolerogenic mechanisms have gradually brought immunotherapy into the arena of cancer therapy. Positive and negative components that, respectively, enhance and suppress immune responses are present in the immune system, as in other physiological systems, and are responsible for maintaining homeostasis. The primordial positive component that triggers virtually any type of immune response is innate immunity. The main reason why the immune system efficiently combats pathogens is that innate immune cells express an abundant array of receptors that recognize various molecules found in microbes. Such recognition provokes intense inflammatory responses and the activation of dendritic cells (DCs), the most potent antigen-presenting cells for T cells. Inflammation and activated DCs subsequently initiate effective antigen-specific immune responses, that is, adaptive immunity. This ‘‘innate immunity-DC-adaptive immunity’’ axis is the essence of the positive immune component. To prevent immune responses to autologous or innocuous antigens, and to avoid excessive responses to noxious antigens, the immune system has several layers of negative (suppressive) components. First of these is the induction of central tolerance in the thymus, through which high-affinity self-reactive T cells are eliminated. To assure tolerance to innocuous antigens in the periphery, peripheral tolerance is maintained by several mechanisms, among which regulatory T cells play a key role. Furthermore, negative signals transmitted to T cells through inhibitory receptors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1), represent crucial molecular mechanisms for the timely termination of T cell responses [1]. In addition, tumor tissues co-opt certain immunosuppressive components, including regulatory T cells, PD-1 ligands, and myeloid-derived suppressor cells, thus creating a microenvironment hostile to tumorreactive T cells. These positive and negative components provide targets for provoking antitumor immune responses. In this issue, Dr. Bocchia reviews peptide vaccines derived from antigens that are preferentially expressed by tumor cells, thus N. Kadowaki (&) Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan e-mail: kadowaki@kuhp.kyoto-u.ac.jp

Late-onset myasthenia gravis – CTLA4low genotype association and low-for-age thymic output of naïve T cells

Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG – its associations with the CTLA4high/gain-of-function +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4low +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of ‘true LOMG’ and an LOMG/early-onset MG overlapping group of patients between 40 and 60.

Epithelial cytoprotection sustains ectopic expression of tissue-restricted antigens in the thymus during murine acute GVHD

AbstractDevelopment of acute graft-versus-host disease (aGVHD) predisposes to chronic GVHD with autoimmune manifestations. A characteristic of experimental aGVHD is the de novo generation of autoreactive T cells. Central tolerance is dependent on the intrathymic expression of tissue-restricted peripheral self-antigens (TRA), which is in mature medullary thymic epithelial cells (mTEChigh) partly controlled by the autoimmune regulator (Aire). Because TECs are targets of donor T-cell alloimmunity, we tested whether murine aGVHD interfered with the capacity of recipient Aire+mTEChigh to sustain TRA diversity. We report that aGVHD weakens the platform for central tolerance induction because individual TRAs are purged from the total repertoire secondary to a decline in the Aire+mTEChigh cell pool. Peritransplant administration of an epithelial cytoprotective agent, fibroblast growth factor-7, maintained a stable pool of Aire+mTEChigh, with an improved TRA transcriptome despite aGVHD. Taken together, our data provide a mechanism for how autoimmunity may develop in the context of antecedent alloimmunity.

Characterization of Human Thymic Exosomes

Exosomes are nanosized membrane-bound vesicles that are released by various cell types and are capable of carrying proteins, lipids and RNAs which can be delivered to recipient cells. Exosomes play a role in intercellular communication and have been described to mediate immunologic information. In this article we report the first isolation and characterization of exosomes from human thymic tissue. Using electron microscopy, particle size determination, density gradient measurement, flow cytometry, proteomic analysis and microRNA profiling we describe the morphology, size, density, protein composition and microRNA content of human thymic exosomes. The thymic exosomes share characteristics with previously described exosomes such as antigen presentation molecules, but they also exhibit thymus specific features regarding surface markers, protein content and microRNA profile. Interestingly, thymic exosomes carry proteins that have a tissue restricted expression in the periphery which may suggest a role in T cell selection and the induction of central tolerance. We speculate that thymic exosomes may provide the means for intercellular information exchange necessary for negative selection and regulatory T cell formation of the developing thymocytes within the human thymic medulla.

Three-Dimensional Visualization of the Mouse Thymus Organization in Health and Immunodeficiency

Lymphoid organs exhibit complex structures tightly related to their function. Surprisingly, although the thymic medulla constitutes a specialized microenvironment dedicated to the induction of T cell tolerance, its three-dimensional topology remains largely elusive because it has been studied mainly in two dimensions using thymic sections. To overcome this limitation, we have developed an automated method for full organ reconstruction in three dimensions, allowing visualization of intact mouse lymphoid organs from a collection of immunolabeled slices. We validated full organ reconstruction in three dimensions by reconstructing the well-characterized structure of skin-draining lymph nodes, before revisiting the complex and poorly described corticomedullary organization of the thymus. Wild-type thymi contain ~200 small medullae that are connected to or separated from a major medullary compartment. In contrast, thymi of immunodeficient Rag2(-/-) mice exhibit only ~20 small, unconnected medullary islets. Upon total body irradiation, medullary complexity was partially reduced and then recovered upon bone marrow transplantation. This intricate topology presents fractal properties, resulting in a considerable corticomedullary area. This feature ensures short distances between cortex and medulla, hence efficient thymocyte migration, as assessed by mathematical models. Remarkably, this junction is enriched, particularly in neonates, in medullary thymic epithelial cells expressing the autoimmune regulator. The emergence of a major medullary compartment is induced by CD4(+) thymocytes via CD80/86 and lymphotoxin-α signals. This comprehensive three-dimensional view of the medulla emphasizes a complex topology favoring efficient interactions between developing T cells and autoimmune regulator-positive medullary thymic epithelial cells, a key process for central tolerance induction.

Aire’s plant homeodomain(PHD)-2 is critical for induction of immunological tolerance

Aire impacts immunological tolerance by regulating the expression of a large set of genes in thymic medullary epithelial cells, thereby controlling the repertoire of self-antigens encountered by differentiating thymocytes. Both humans and mice lacking Aire develop multiorgan autoimmunity. Currently, there are few molecular details on how Aire performs this crucial function. The more amino-terminal of its two plant homeodomains (PHDs), PHD1, helps Aire target poorly transcribed loci by "reading" the methylation status of a particular lysine residue of histone-3, a process that does not depend on the more carboxyl-terminal PHD-2. This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice. PHD2 was required for Aire to interact with sets of protein partners involved in chromatin structure/binding or transcription but not with those implicated in pre-mRNA processing; it also was not required for Aire's nuclear translocation or regional distribution. PHD2 strongly influenced the ability of Aire to regulate the medullary epithelial cell transcriptome and so was crucial for effective central tolerance induction. Thus, Aire's two PHDs seem to play distinct roles in the scenario by which it assures immunological tolerance.

The Many Faces of Aire in Central Tolerance

Although the role that Autoimmune Regulator (Aire) plays in the induction of central tolerance is well known, the precise cellular and molecular mechanisms are still unclear and debated. In the prevailing view, Aire serves mainly as a direct inducer of tissue-specific antigens. However, there is a growing amount of evidence suggesting that Aire modulates the differentiation program of medullary thymic epithelial cells, which may directly contribute to the negative selection of self-reactive thymocytes. In addition, Aire has been shown to regulate the expression of many intrathymic chemokines that are required for the proper localization of thymocytes and dendritic cells, and thus are potentially important for direct and indirect self-antigen presentation in the thymic medulla. Further, recent evidence suggests that the induction of certain antigen-specific regulatory T-cells that translocate to tumors and peripheral tissues can be Aire dependent and may contribute to tissue-specific tolerance. This review summarizes the current understanding of the effects of Aire on these alternative mechanisms for the induction of Aire-induced central tolerance.

Does citrullination occur in medullary thymic epithelial cells?

Event Abstract Back to Event Does citrullination occur in medullary thymic epithelial cells? Robby Engelmann1*, Andra Biemelt1, Anja Johl1 and Brigitte Müller-Hilke1 1 University Medicine Rostock, Institute of Immunology, Germany Introduction The presence of antibodies against citrullinated peptide antigens (ACPA) is a hallmark of rheumatoid arthritis. However, it is unclear how these autoantibodies develop. It has been proposed, that peripheral citrullination generates neoepitopes that are favored targets of autoreactive immune cells evading central tolerance induction. We investigated the expression of peptidyl arginine deiminases (PAD) in medullary thymic epithelial cells (mTEC). Methods Thymic epithelial cells were isolated from 4-5 weeks old mice susceptible (DBA/1) or not susceptible (NMRI, C57BL/6) for collagen-induced arthritis (CIA). After TEC-enrichment by percoll density gradient centrifugation and magnetic depletion of CD45+ cells, immature mTEC (CD45-EpCAM+CD80lowLy-51-) and mature mTEC (CD45-EpCAM+CD80highLy-51-) were FACS-sorted. Cortical TEC were identified as CD45-EpCAM+CD80-Ly-51+. mRNA and protein were isolated from sorted mTEC populations for subsequent expression analysis. Results Flow cytometry analysis revealed a significantly decreased number of mTEC in thymi of CIA-susceptible DBA/1 mice in comparison to NMRI and C57BL/6 mice, whereas the number of T cells and cTEC did not show any differences. Subsequent quantitative PCR confirmed cell identity since mature mTEC showed significantly elevated expression of aire and the tissue restricted gene insulin2 compared to immature ones. Pad expression was higher in mature mTEC compared to immature mTEC and correlated well with the expression of aire. Furthermore, the expression of pad6 was significantly elevated in DBA/1 mature mTEC. Conclusion Pad genes are readily expressed at RNA level in murine mTEC. However, it remains to be determined whether PAD protein and citrullination can also be found in mTEC. This is work in progress. Keywords: citrullination, neoepitopes, collagen-induced arthritis, Central Tolerance, Thymus Gland Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Engelmann R, Biemelt A, Johl A and Müller-Hilke B (2013). Does citrullination occur in medullary thymic epithelial cells?. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00674 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Robby Engelmann, University Medicine Rostock, Institute of Immunology, Rostock, Germany, robby.engelmann@med.uni-rostock.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Robby Engelmann Andra Biemelt Anja Johl Brigitte Müller-Hilke Google Robby Engelmann Andra Biemelt Anja Johl Brigitte Müller-Hilke Google Scholar Robby Engelmann Andra Biemelt Anja Johl Brigitte Müller-Hilke PubMed Robby Engelmann Andra Biemelt Anja Johl Brigitte Müller-Hilke Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

MicroRNAs Control the Maintenance of Thymic Epithelia and Their Competence for T Lineage Commitment and Thymocyte Selection

Thymic epithelial cells provide unique cues for the lifelong selection and differentiation of a repertoire of functionally diverse T cells. Rendered microRNA (miRNA) deficient, these stromal cells in the mouse lose their capacity to instruct the commitment of hematopoietic precursors to a T cell fate, to effect thymocyte positive selection, and to achieve promiscuous gene expression required for central tolerance induction. Over time, the microenvironment created by miRNA-deficient thymic epithelia assumes the cellular composition and structure of peripheral lymphoid tissue, where thympoiesis fails to be supported. These findings emphasize a global role for miRNA in the maintenance and function of the thymic epithelial cell scaffold and establish a novel mechanism how these cells control peripheral tissue Ag expression to prompt central immunological tolerance.

Oligodendrocytes Enforce Immune Tolerance of the Uninfected Brain by Purging the Peripheral Repertoire of Autoreactive CD8+ T Cells

Myelin-specific CD8(+) Tcells are thought to contribute to the pathogenesis of multiple sclerosis. Here we modeled this contribution in mice with CD8(+) Tcells recognizing ovalbumin (OVA) expressed in oligodendrocytes (ODCs). Surprisingly, even very high numbers of activated OVA-reactive CD8(+) Tcells failed to induce disease and were cleared from the immune system after antigen encounter inthe centralnervous system (CNS). Peripheral infection with OVA-expressing Listeria (Lm-OVA) enabled CD8(+) Tcells to enter the CNS, leading to the deletion of OVA-specific clones after OVA recognition on ODCs. In contrast, intracerebral infection allowed OVA-reactive CD8(+) Tcells to cause demyelinating disease. Thus, in response to infection, CD8(+) Tcells also patrol the CNS. If the CNS itself is infected, they destroy ODCs upon cognate antigen recognition in pursuit of pathogen eradication. In the sterile brain, however, antigen recognition on ODCs results in their deletion, thereby maintaining tolerance.