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Narcolepsy is a rare chronic neurological disorder characterized by an irresistible excessive daytime sleepiness and cataplexy. The disease is considered to be the result of the selective disruption of neuronal cells in the lateral hypothalamus expressing the neuropeptide hypocretin, which controls the sleep-wake cycle. Diagnosis and management of narcolepsy represent still a substantial medical challenge due to the large heterogeneity in the clinical manifestation of the disease as well as to the lack of understanding of the underlying pathophysiological mechanisms. However, significant advances have been made in the last years, thus opening new perspective in the field. This review describes the current knowledge of clinical presentation and pathology of narcolepsy as well as the existing diagnostic criteria and therapeutic intervention for the disease management. Recent evidence on the potential immune-mediated mechanisms that may underpin the disease establishment and progression are also highlighted. [ABSTRACT FROM AUTHOR]

This article is a contribution to the special issue on: Heterogeneity of tissue-resident immunity across organs and in health and disease - Guest Editors: Federica Sallusto & Petra Arck The conception of how the immune system is operational has been significantly better understood in recent years. Thus, tissue-resident memory T cells are potentially endowed with the capacity to protect against the reemergence of cancer cells. For example, tissue-resident memory T cells are diminished in airway tissues of neonates, compared to older children or adults, which hampers the ability to make specific recall responses after secondary infectious challenges. [Extracted from the article]

Using granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 we have established dendritic cell (DC) lines from blood mononuclear cells that maintain the antigen capturing and processing capacity characteristic of immature dendritic cells in vivo. These cells have typical dendritic morphology, express high levels of major histocompatibility complex (MHC) class I and class II molecules, CD1, Fcγ RII, CD40, B7, CD44, and ICAM-1, and lack CD14. Cultured DCs are highly stimulatory in mixed leukocyte reaction (MLR) and are also capable of triggering cord blood naive T cells. Most strikingly, these DCs are as efficient as antigen-specific B cells in presenting tetanus toxoid (TT) to specific T cell clones. Their efficiency of antigen presentation can be further enhanced by specific antibodies via FcR-mediated antigen uptake. Incubation of these cultured DCs with tumor necrosis factor α (TNF-α) or soluble CD40 ligand (CD40L) for 24 h results in an increased surface expression of MHC class I and class II molecules, B7, and ICAM-1 and in the appearance of the CD44 exon 9 splice variant (CD44-v9); by contrast, FcγRII is markedly and sometimes completely downregulated. The functional consequences of the short contact with TNF-α are in increased T cell stimulatory capacity in MLR, but a 10-fold decrease in presentation of soluble TT and a 100-fold decrease in presentation of TT-immunoglobulin G complexes. [ABSTRACT FROM AUTHOR]

B Correction to: Seminars in Immunopathology b https://doi.org/10.1007/s00281-022-00933-9 In the original version of this article, the given and family names of Federica Sallusto were incorrectly structured. The original article can be found online at https://doi.org/10.1007/s00281-022-00933-9. [Extracted from the article]

CD4+ T helper (Th) cells play a central role in the adaptive immune response by providing help to B cells and cytotoxic T cells and by releasing different types of cytokines in tissues to mediate protection against a wide range of pathogenic microorganisms. These functions are performed by different types of Th cells endowed with distinct migratory capacities and effector functions. Here we discuss how studies of the human T cell response to microbes have advanced our understanding of Th cell functional heterogeneity, in particular with the discovery of a distinct Th1 subset involved in the response to Mycobacteria and the characterization of two types of Th17 cells specific for extracellular bacteria or fungi. We also review new approaches to dissect at the clonal level the human CD4+ T cell response induced by pathogens or vaccines that have revealed an unexpected degree of intraclonal diversification and propose a progressive and selective model of CD4+ T cell differentiation. [ABSTRACT FROM AUTHOR]

The article introduces scientific conference papers on T cells and skin to be presented at the 22nd Scientific meeting 2014 of the Fondation René Touraine (FRT), a European non-governmental organization that promotes therapeutic progress in dermatology, on 5th December 2014 in Paris, France. Papers by researchers Shimon Sakaguchi, Federica Sallusto and Thomas Gebhardt are included. Specific topics include immune abnormalities found in atopic dermatitis and adoptive transfer of dendritic cells.

Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells1,2. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues3-6. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response7-9. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (Tcm) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response. [ABSTRACT FROM AUTHOR]

To perform their distinct effector functions, pathogen-specific T cells have to migrate to target tissue where they recognize antigens and produce cytokines that elicit appropriate types of protective responses. Similarly, migration of pathogenic self-reactive T cells to target organs is an essential step required for tissue-specific autoimmunity. In this article, we review data from our laboratory as well as other laboratories that have established that effector function and migratory capacity are coordinately regulated in different T-cell subsets. We then describe how pathogenic T cells can enter into intact or inflamed central nervous system (CNS) to cause experimental autoimmune encephalomyelitis or multiple sclerosis. In particular, we elaborate on the role of CCR6/CCL20 axis in migration through the choroid plexus and the involvement of this pathway in immune surveillance of and autoimmunity in the CNS. [ABSTRACT FROM AUTHOR]

There is growing consensus for an urgent need to develop efficient methods to analyze the human T and B cell response in order to understand its regulation, to unravel host-pathogen interactions and to design better vaccines. In this review we will consider different methods that have been developed to analyze human T and B cells and focus in particular on those based on high-throughput cell culture, such as memory B cell immortalization, plasma cell cultures and libraries of naïve or memory T cells. These culture-based methods can be used to interrogate with high efficiency the immune repertoires in order to characterize the frequency, function and specificity of naïve or memory T cells and to isolate potent and broadly neutralizing monoclonal antibodies. [Copyright &y& Elsevier]

Vaccines work by eliciting an immune response and consequent immunological memory that mediates protection from infection or disease. Recently, new methods have been developed to dissect the immune response in experimental animals and humans, which have led to increased understanding of the molecular mechanisms that control differentiation and maintenance of memory T and B cells. In this review we will provide an overview of the cellular organization of immune memory and underline some of the outstanding questions on immunological memory and how they pertain to vaccination strategies. Finally we will discuss how we can learn about antigen design from the interrogation of our memory T and B cells—a journey from vaccines to memory and back. [ABSTRACT FROM AUTHOR]

Following an immune response two types of differentiated B cells persist in the memory pool: plasma cells, which confer immediate protection by the secretion of specific antibodies; and memory B cells, which confer rapid and enhanced response to secondary challenge. We will review recent advances in understanding the heterogeneity, dynamics, and persistence of human memory B cells and plasma cells as well as new methods to isolate human monoclonal antibodies. These findings offer new insights into the human B cell response, which are relevant for vaccination and therapeutic intervention. [Copyright &y& Elsevier]

Abstract: IL-17-producing T cells (Th17) have been identified in mice as a distinct lineage of CD4+ T helper cells. Since their discovery, efforts have been made in characterizing human Th17 cells and the factors involved in their differentiation and in understanding the role these cells play in protective immunity and autoimmune diseases. [Copyright &y& Elsevier]

Twenty years after the discovery of chemokines is an appropriate time to review leukocyte traffic and to assess the knowledge and opportunities that have arisen from countless studies of the large and tight-knit family of chemotactic proteins. [ABSTRACT FROM AUTHOR]

In the course of the immune response against microbes, naïve I cells proliferate and generate varied classes of effector cells, as well as memory cells with distinct properties and functions. Owing to recent technological advances, some of the most imposing questions regarding effector and memory I cell differentiation are now becoming experimentally soluble: How many classes of antigen-specific I cells exist, and how malleable are they in their fate and in their functional state? How might a spectrum of cell fates be imparted to the clonal descendants of a single Lymphocyte? Where, when, and how does pathogen-associated information refine the instruction, selection, and direction of newly activated I cells as they perform their tasks in different Locations and times? Some surprising new glimpses ahead on these subjects and other yet-unanswered questions are discussed. [ABSTRACT FROM AUTHOR]

It has been known for almost 30 years that mouse B cells proliferate and differentiate to antibody-secreting cells when stimulated by microbial products such as lipopolysaccharide or CpG-containing DNA, but the relevance of these polyclonal responses remained elusive until recently. A breakthrough in the field has been the discovery of endosomal Toll-like receptors in B cells and their role in the production of autoantibodies. Since then, several reports have extended the role of Toll-like receptors in B-cell responses to thymus-independent and thymus-dependent antigens, and in antibody class switch in lymphoid and extralymphoid tissues. Considering the complexity of the system it is perhaps not surprising that the literature contains some contradictory findings. However, the scientific fecundity in this rapidly evolving field will probably give rise to discoveries that could be translated into more effective vaccines and immunotherapies. [Copyright &y& Elsevier]

Memory T cells can be broadly divided into central memory and effector memory subsets, which are endowed with different capacities to home to lymphoid or non-lymphoid tissues, to proliferate in response to antigen or cytokines and to perform effector functions. In the past few years progress has been made in understanding the properties of these memory T cell subsets and, in particular, the signals required for their generation and maintenance. Collectively these data point to a critical role of central memory T cells in conferring long-term immunity. [Copyright &y& Elsevier]

The study of leukocyte migration continues to provide new insights into the regulation of lymphocyte priming in secondary lymphoid organs and effector responses in inflamed tissues. Chemoattractant receptors have always been viewed as facilitators of cell movement into a tissue. This whole concept must now be revised with the discovery of sphingosine 1 phosphate receptors, which control cell exit from lymphoid tissues. The chemoattractants that regulate lymphoid tissue homing are usually different to those that regulate leukocyte recruitment to inflamed tissues. There is evidence, however, of inflammatory pathways of leukocyte recruitment in lymph nodes and, conversely of constitutive pathways in peripheral tissues. Finally, antagonists (or agonists) of chemoattractant receptors and their signalling pathways represent the most attractive strategy for the treatment of a wide range of inflammatory diseases, including allergy. [Copyright &y& Elsevier]

The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice. [ABSTRACT FROM AUTHOR]

Two potential outcomes confront proliferating antigen-stimulated naive T cells: differentiation to effector and memory cells, or deletion. How stimulation affects cell fate is unclear. Autonomous CD8[SUP+] T cell differentiation has been proposed, but this does not explain the abortive proliferation of T cells induced by immature dendritic cells. Here we show that human and mouse CD4[SUP+] and CD8[SUP+] T cells receiving short or weak stimulation of the T cell receptor proliferate in response to interleukin 2 (IL-2) but are not 'fit' because they die by neglect, fail to proliferate in response to IL-7 and IL-I5 and disappear in vivo. Conversely, prolonged or strong stimulation promotes 'fitness' by enhancing survival and cytokine responsiveness. Our results are consistent with the concept that signal strength drives progressive T cell differentiation and the acquisition of fitness. [ABSTRACT FROM AUTHOR]

T cells are stimulated by stochastic exposure to antigen-presenting cells and cytokines. We review evidence that the level of signal that is accumulated determines progression through hierarchical thresholds for proliferation and differentiation, leading to the generation of various intermediates and effector T cells. These cells are then selected to enter the memory pool according to their fitness — that is, their capacity to access and use survival signals. We suggest that the intermediates that are generated by antigenic stimulation of T and B cells persist as central memory cells, which can mount secondary responses to antigen and maintain appropriate levels of effector cells and antibodies throughout the lifetime of an individual. [ABSTRACT FROM AUTHOR]

Discusses how dendritic cells (DC) provide a quantitative and qualitative framework for T cell antigen recognition. Requirements for activation and differentiation of naive T cells; Mechanism by which DC assembles the components into discrete packets; Determination of magnitude and class of T cell responses.

Naïve T lymphocytes sense foreign antigens by establishing contacts with dendritic cells (DCs). At the immunological synapse between the T cell and a DC, T cell receptors (TCRs) are serially engaged and triggered by specific ligands. The amount and duration of TCR triggering and the efficiency of signal amplification determine T cell commitment to proliferation and differentiation. The nature and availability of DCs bearing antigen and costimulatory molecules shape the T cell response, giving rise to distinct functional outputs such as effector and memory T cell generation or T cell tolerance. [ABSTRACT FROM AUTHOR]

Focuses on a study which discussed how the dynamics of antigen-loaded dendritic cells (DC) encounter antigen-specific T cells and the mechanism of T cell differentiation that make the decoding of the packets of information stochastic rather than determinate. Description and function of DC; Information on the T cell activation and differentiation programs; Details on linear T cell differentiation; Dynamics of primary responses.

The immune response requires a timely interaction among different cell types within distinct microenvironments. Our studies have focused on the regulation of chemokine receptors in dendritic cells (DC) and T lymphocytes. Chemokine receptors expressed by immature DC promote their migration to inflamed tissues where antigens are captured and maturation is induced. Maturing DC upregulate CCR7, which drives their migration to the T-cell areas of the draining lymph nodes where antigen is presented to naïve T cells. DC produce a variety of chemokines that influence DC recruitment into inflamed tissues and DC-T cell interaction in the lymph nodes. Chemokine receptors are differentially acquired by developing Th1 and Th2 cells and are differentially expressed on subsets of "central memory" and "effector memory" T cells. Furthermore, following antigenic stimulation, effector T cells can rapidly switch chemokine receptor expression, acquiring new migratory capacities. These studies provide insights into the mechanisms that control T-cell priming as well as memory and effector immune responses. [ABSTRACT FROM AUTHOR]

Explores the role of chemokine receptor expression in control priming, effector function and memory responses. Discussion on chemokine and chemokine receptors in homeostasis and inflammation; Influence of chemokines on T and B cell development; Role of chemokines in effector and memory responses.

Originally published as 401, 708?712; 1999Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response. [ABSTRACT FROM AUTHOR]

Attempts to show that the chemokine receptor CCR7 divides human memory T cells into two functionally distinct subsets. Involvement of chemokine receptors and adhesion molecules in lymphocyte migration to secondary lymphoid organs; T-cell help for dendritic cells and B cells.

The article reviews the results of almost two years of COVID-19 immunology research and discusses definitive findings and remaining questions regarding the understanding of COVID-19 pathophysiology. It examines the emerging understanding of differences in immune responses seen in those with and without Long Covid syndrome. It mentions that the knowledge gained from this COVID-19 research will be applied in studies of inflammatory processes involved in critical and chronic illnesses.

Considerable research effort has been made worldwide to decipher the immune response triggered upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, identify the drivers of severe and fatal COVID-19, and understand what leads to the prolongation of symptoms after disease resolution. We review the results of almost 2 years of COVID-19 immunology research and discuss definitive findings and remaining questions regarding our understanding of COVID-19 pathophysiology. We discuss emerging understanding of differences in immune responses seen in those with and without Long Covid syndrome, also known as post-acute sequelae of SARS-CoV-2. We hope that the knowledge gained from this COVID-19 research will be applied in studies of inflammatory processes involved in critical and chronic illnesses, which remain a major unmet need. [ABSTRACT FROM AUTHOR]

The article reports on the regulation of gene activation and silencing in helper T cells. It provides a framework for understanding the very nature of polarity and plasticity of helper T cell fates at different stages of immunity and in different species. Helper T cell effector fate, which can be studied in vitro and in vivo, can provide a paradigm for regulated and heritable alterations of gene activity. Covalent modifications of DNA and histones, as well as the three dimensional structure of chromatin fibers and chromosomes, can influence eukaryotic gene activity. This regulation is likely to occur both in normal development and homeostasis and in pathological situations, such as the silencing of tumor suppressor genes that might lead to cancerous transformation. The feasibility of investigating these issues using immunological model systems should make for exciting advances in an area that is likely to be relevant across many biological systems, physiological and pathological. Furthermore, a deeper understanding of our genomic filing systems should offer new therapeutic strategies to alter apparently fixed cell fates, in the immune system and elsewhere.

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Reports on research in which the human eotaxin receptor (CCR3) was found to be expressed by TH2 cells. How the attraction of TH2 cells by eotaxin could represent a key mechanism in allergic reactions; Reasons for this hypothesis.

In this article, the authors discuss the study of L. Gattinoni and colleagues on memory stem cells (TSCM). The authors say that the study, which was published in the October 2011 issue of the journal "Nature Medicine," reports the identification of such cells in humans, describing them "disguised" as naive for expressing CD4RA and other markers characteristic of naive T cells. They suggest that their findings raise the development of new strategies for antitumor adoptive cell therapy.

Dendritic cells are professional antigen-presenting cells that mediate immunity and tolerance. uncover a new route for dendritic cell production in vivo. They show that in response to infection by gram-negative bacteria, monocytes are recruited to the lymph node where they rapidly differentiate into dendritic cells that present antigens to T cells. [Copyright &y& Elsevier]

The interaction between dendritic cells and T cells is critical for induction of appropriate immune responses. Visualization of their interaction in intact lymph nodes provides insight into the process of generating immunity or tolerance. [ABSTRACT FROM AUTHOR]

Chemokine receptor nanoscale organization at the cell membrane is orchestrated by the actin cytoskeleton and influences cell responses. Using single-particle tracking analysis we show that CXCR4R334X, a truncated mutant chemokine receptor linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), fails to nanoclusterize after CXCL12 stimulation, and alters the lateral mobility and spatial organization of CXCR4 when coexpressed. These findings correlate with multiple phalloidin-positive protrusions in cells expressing CXCR4R334X, and their inability to correctly sense chemokine gradients. The underlying mechanisms involve inappropriate actin cytoskeleton remodeling due to the inadequate ß-arrestin1 activation by CXCR4R334X, which disrupts the equilibrium between activated and deactivated cofilin. Overall, we provide insights into the molecular mechanisms governing CXCR4 nanoclustering, signaling and cell function, and highlight the essential scaffold role of ß-arrestin1 to support CXCL12-mediated actin reorganization and receptor clustering. These defects associated with CXCR4R334X expression might contribute to the severe immunological symptoms associated withWHIM syndrome. [ABSTRACT FROM AUTHOR]

The administration of hyper immune sera to prevent or treat life-threatening infections is a remarkable milestone in medicine and biotechnology that has been achieved more than a century ago. Yet, the therapeutic use of monoclonal antibodies in this field has developed slowly over the last decades. Here we compare and contrast current methods to generate human monoclonal antibodies and highlight the advantages of exploiting the human antibody repertoire using a novel method that allows efficient immortalization and cloning of human memory B cells. This method, which has been successfully applied to isolate broadly neutralizing antibodies against SARS and H5N1 influenza viruses, is expected to accelerate the development of therapeutics in the field of infectious diseases not only by providing neutralizing antibodies for passive serotherapy, but also by generating relevant information for vaccine design. [Copyright &y& Elsevier]

The identification of CD4+ T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here, we demonstrate in COVID-19–recovered individuals a robust CD4+ T cell response to naturally processed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that the receptor-binding domain (RBD) is highly immunogenic and that 33% of RBD-reactive clones and 94% of individuals recognized a conserved immunodominant S346–S365 region comprising nested human leukocyte antigen DR (HLA-DR)– and HLA-DP–restricted epitopes. Using pre– and post– COVID-19 samples and S proteins from endemic coronaviruses, we identified cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature ThCD103 and ThGM cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) is the primary viral cause of congenital birth defects and causes significant morbidity and mortality in immune-suppressed transplant recipients. Despite considerable efforts in vaccine development, HCMV infection still represents an unmet clinical need. In recent phase II trials, a MF59-adjuvanted gB vaccine showed only modest efficacy in preventing infection. These findings might be attributed to low level of antibodies (Abs) with a neutralizing activity induced by this vaccine. Here, we analyzed the immunogenicity of each gB antigenic domain (AD) and demonstrated that domain I of gB (AD5) is the main target of HCMV neutralizing antibodies. Furthermore, we designed, characterized and evaluated immunogenic responses to two different nanoparticles displaying a trimeric AD5 antigen. We showed that mice immunization with nanoparticles induces sera neutralization titers up to 100-fold higher compared to those obtained with the gB extracellular domain (gBECD). Collectively, these results illustrate with a medically relevant example the advantages of using a general approach combining antigen discovery, protein engineering and scaffold presentation for modern development of subunit vaccines against complex pathogens. Author summary: Human cytomegalovirus (HCMV) infection is the foremost viral cause of congenital birth defects. Attempts to vaccinate against HCMV brought moderate, though not sufficient, reduction in infection. Moreover, phase II clinical trial with gB formulated in MF59 adjuvant did not induce a neutralizing antibody response. Here, we identify the antigenic domain 5 (AD5) of gB as the target of most neutralizing antibodies. Moreover, functionalization of AD5 on self-assembling nanoparticles leads to a gB vaccine candidates generating high antibody binding and neutralizing titers. Interestingly, it was recently reported that most antibodies targeting AD5 could inhibit cell fusion, a discovery on interest as HCMV is thought to disseminate within the host primarily through direct cell-to-cell spreading. Our data not only provides new vaccine candidates but may also have important implications for understanding cellular fusion promoted by HCMV. [ABSTRACT FROM AUTHOR]

In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A–induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation. [ABSTRACT FROM AUTHOR]

Background: The brain barriers establish compartments in the central nervous system (CNS) that significantly differ in their communication with the peripheral immune system. In this function they strictly control T-cell entry into the CNS. T cells can reach the CNS by either crossing the endothelial blood–brain barrier (BBB) or the epithelial blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP). Objective: Analysis of the cellular and molecular mechanisms involved in the migration of different human CD4+ T-cell subsets across the BBB versus the BCSFB. Methods: Human in vitro models of the BBB and BCSFB were employed to study the migration of circulating and CNS-entry experienced CD4+ T helper cell subsets (Th1, Th1*, Th2, Th17) across the BBB and BCSFB under inflammatory and non-inflammatory conditions in vitro. Results: While under non-inflammatory conditions Th1* and Th1 cells preferentially crossed the BBB, under inflammatory conditions the migration rate of all Th subsets across the BBB was comparable. The migration of all Th subsets across the BCSFB from the same donor was 10- to 20-fold lower when compared to their migration across the BBB. Interestingly, Th17 cells preferentially crossed the BCSFB under both, non-inflamed and inflamed conditions. Barrier-crossing experienced Th cells sorted from CSF of MS patients showed migratory characteristics indistinguishable from those of circulating Th cells of healthy donors. All Th cell subsets could additionally cross the BCSFB from the CSF to ChP stroma side. T-cell migration across the BCSFB involved epithelial ICAM-1 irrespective of the direction of migration. Conclusions: Our observations underscore that different Th subsets may use different anatomical routes to enter the CNS during immune surveillance versus neuroinflammation with the BCSFB establishing a tighter barrier for T-cell entry into the CNS compared to the BBB. In addition, CNS-entry experienced Th cell subsets isolated from the CSF of MS patients do not show an increased ability to cross the brain barriers when compared to circulating Th cell subsets from healthy donors underscoring the active role of the brain barriers in controlling T-cell entry into the CNS. Also we identify ICAM-1 to mediate T cell migration across the BCSFB. [ABSTRACT FROM AUTHOR]

Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep-wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the 'narcoleptic borderland', including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed. [ABSTRACT FROM AUTHOR]