Explore the vast range of titles available.

In recent years, the understanding of regulatory T cell (T reg cell) biology has expanded considerably. Key observations have challenged the traditional definition of T reg cells and have provided insight into the underlying mechanisms responsible for the development of autoimmune diseases, with new therapeutic strategies that improve disease outcome. This Review summarizes the newer concepts of T reg cell instability, T reg cell plasticity and tissue-specific T reg cells, and their relationship to autoimmunity. Those three main concepts have changed the understanding of T reg cell biology: how they interact with other immune and non-immune cells; their functions in specific tissues; and the implications of this for the pathogenesis of autoimmune diseases. T reg cells have a critical role in maintaining peripheral tolerance. In this Focus Review, Dominguez-Villar and Hafler describe how the instability and plasticity of T reg cells can contribute to the breakdown of tolerance and lead to autoimmune disease.

The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.In this Review, the authors discuss the origins of regulatory T (Treg) cells in the periphery and the mechanisms by which Treg cells are induced, as well as the regulation of the suppressive function of these cells. Moreover, they examine evidence for and mechanisms of Treg cell dysfunction in common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.

In mice, T regulatory (T reg ) cells show considerable phenotypic and functional plasticity. David Hafler and his colleagues report that the frequency of human T reg cells expressing IFN-γ is increased in the peripheral blood of individuals with multiple sclerosis. These T reg cells possess reduced suppressive activity, and in vitro studies suggest that IL-12 promotes the development of a T helper type 1–like phenotype. CD4 + CD25 high CD127 low/– forkhead box p3 (Foxp3) + regulatory T cells (T reg cells) possess functional plasticity. Here we describe a higher frequency of T helper type 1 (T H 1)-like, interferon-γ (IFN-γ)-secreting Foxp3 + T cells in untreated subjects with relapsing remitting multiple sclerosis (RRMS) as compared to healthy control individuals. In subjects treated with IFN-β, the frequency of IFN-γ + Foxp3 + T cells is similar to that in healthy control subjects. In vitro , human T reg cells from healthy subjects acquire a T H 1-like phenotype when cultured in the presence of interleukin-12 (IL-12). T H 1-like T reg cells show reduced suppressive activity in vitro , which can partially be reversed by IFN-γ–specific antibodies or by removal of IL-12.

A 37-year-old man with multiple sclerosis has recurrent disease activity despite several previous therapies. Treatment with fingolimod is recommended. Fingolimod blocks the egress of lymphocytes from lymph nodes, preventing them from reaching the central nervous system. Foreword This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations. Stage A 37-year-old man with multiple sclerosis was evaluated for consideration of oral immunotherapy. Six years earlier, he had reported acute monocular visual disturbance. The diagnosis of multiple sclerosis was subsequently confirmed by means of examination of cerebrospinal fluid, which revealed an increased IgG index and oligoclonal banding, and by abnormal results on magnetic resonance imaging (MRI). There was no family history of multiple sclerosis. Daily injections of glatiramer acetate were initiated at the time of diagnosis, but two consecutive annual brain MRI scans revealed substantial disease activity. He was then switched to interferon beta therapy, but this treatment was . . .

Many deep learning-based methods have been proposed to handle complex single-cell data. Deep learning approaches may also prove useful to jointly analyze single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) data for novel discoveries. We developed scNAT, a deep learning method that integrates paired scRNA-seq and scTCR-seq data to represent data in a unified latent space for downstream analysis. We demonstrate that scNAT is capable of removing batch effects, and identifying cell clusters and a T cell migration trajectory from blood to cerebrospinal fluid in multiple sclerosis.

Key Points Regulatory T (T Reg ) cells are potent mediators of dominant tolerance in the periphery. The study of T Reg cells in many models of animal disease has revealed their ability to prevent autoimmune pathogenesis and to restore immune homeostasis but also to promote cancer growth by repressing antitumour immune responses. Such findings have made T Reg cells a promising target for clinical application. Confusion as to the mechanism of the identity, function and stability of human T Reg cells has, to date, impeded the general therapeutic use of these cells. Several recent studies have suggested that human T Reg cells possess functional and phenotypic diversity that has not been previously apparent. Indeed, based on recent findings, forkhead box P3 (FOXP3) + CD4 + T cells can be divided into several functionally unique populations based on their expression of CD45RA, CD45RO, HLA-DR and FOXP3. A more detailed characterization of the ontogeny, phenotype and suppressive function of human T Reg cells is needed for the study of T Reg cells in the pathophysiology of autoimmune diseases, allergy, transplantation, pregnancy, infection and cancer. Although several issues regarding long term reliability and safety still need to be addressed, T Reg cell-based therapy is a promising therapeutic perspective that should be applicable in a wide range of immune diseases. In this article, the authors describe the development, phenotype and suppressive function of human regulatory T cell populations. There has been much emphasis on the clinical use of these cells, and the associated progresses and pitfalls are discussed here. Forkhead box P3 (FOXP3) + regulatory T (T Reg ) cells are potent mediators of dominant self tolerance in the periphery. But confusion as to the identity, stability and suppressive function of human T Reg cells has, to date, impeded the general therapeutic use of these cells. Recent studies have suggested that human T Reg cells are functionally and phenotypically diverse. Here we discuss recent findings regarding human T Reg cells, including the ontogeny and development of T Reg cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by T Reg cell subsets and factors that regulate T Reg cell lineage commitment. We discuss future studies that are needed for the successful therapeutic use of human T Reg cells.

How are autoreactive T cells induced and regulated in patients with autoimmune disease? This question lies at the core of understanding autoimmune disease pathologies, yet it has remained elusive due to host variability and the complexity of the immune system. In this issue of the JCI, Kramer and colleagues used autoimmune hepatitis (AIH) as a model to explore the maintenance of autoreactive CD4+ T cells specific to O-phosphoseryl-tRNA:selenocysteine tRNA synthase (SepSecS). The findings provide insight into the interaction between T cells and B cells in AIH pathogenesis that may reflect a shared mechanism among other autoimmune diseases.

Key Points The prognosis for glioblastoma patients is poor, with median overall survival of approximately 15–17 months Immunotherapy has clinical benefits in other advanced tumours, such as melanoma and lung cancer, for which conventional therapies have had limited success The blood–brain barrier prevents macromolecules from entering the CNS, but readily allows traffic of activated lymphocytes; thus, communication occurs between the CNS and the immune system The success of immunotherapy in other cancers, and the current understanding of the interaction between the brain and the immune system provide a rationale for exploration of immune checkpoint inhibitors in glioblastoma Tumour progression could involve multiple immunosuppressive mechanisms, making combination of immunotherapeutic agents that target different pathways a promising approach Clinical trials evaluating immune checkpoint inhibitors in glioblastoma patients are ongoing Glioblastoma is the most common primary brain tumour in adults, and has a notoriously poor prognosis. Recent successes of immunotherapy in other cancer types have made immunotherapy—particularly the use of immune checkpoint modulators—an appealing strategy against glioblastoma. Here, Matthias Preusser and colleagues summarize current knowledge on immune checkpoint modulators, and evaluate their potential role in glioblastoma treatment in light of preclinical studies and emerging clinical data. Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15–17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.

Key Points MS has been a treatable disease for approximately 20 years, and incremental improvements in treatment options have culminated in remarkable progress for the amelioration of inflammatory aspects of MS Traditionally, three patterns of disease evolution (relapsing–remitting, secondary progressive and primary progressive) were recognized, but present evidence suggests that these differing clinical phenotypes share common pathophysiology A major unmet medical need in MS therapeutics is to define biomarkers to aid selection from the several treatment options so that individual patients can receive optimal personalized therapy The requirement that patients fail IFN-β and glatiramer acetate therapy before being offered alternatives risks irreversible neural tissue injury during the process of initiating appropriate medication Early, general statements that implicated a genetic component in multiple sclerosis (MS) susceptibility have been replaced by the identification of more than 100 genetic variants associated with disease susceptibility, ∼90% of which are noncoding Over half of genetic variants associated with MS risk are also found in other autoimmune diseases, and are primarily associated with genes that regulate immune function The past 20 years have seen remarkable progress in research into multiple sclerosis (MS), resulting in a veritable armamentarium of treatment options. Ransohoff and colleagues reflect on three major eras of drug development to date. The authors also offer guidance on how best to select between various therapeutics, and look to the future of MS research. Multiple sclerosis (MS) has been thought to be a complex and indecipherable disease, and poorly understood with regards to aetiology. Here, we suggest an emphatically positive view of progress over several decades in the understanding and treatment of MS, particularly focusing on advances made within the past 20 years. As with virtually all complex disorders, MS is caused by the interaction of genetic and environmental factors. In recent years, formidable biochemical, bioinformatic, epidemiological and neuroimaging tools have been brought to bear on research into the causes of MS. While susceptibility to the disease is now relatively well accounted for, disease course is not and remains a salient challenge. In the therapeutic realm, numerous agents have become available, reflecting the fact that the disease can be attacked successfully at many levels and using varied strategies. Tailoring therapies to individuals, risk mitigation and selection of first-line as compared with second-line medications remain to be completed. In our view, the MS landscape has been comprehensively and irreversibly transformed by this progress. Here we focus on MS therapeutics—the most meaningful outcome of research efforts.