Neutrophils perform critical functions in the innate response to infection, including through the production of neutrophil extracellular traps (NETs) - web-like DNA structures which are extruded from ...neutrophils upon activation. Elevated levels of NETs have been linked to autoimmunity but this association is poorly understood. By contrast, IL-17 producing Th17 cells are a key player in various autoimmune diseases but are also crucial for immunity against fungal and bacterial infections. Here we show that NETs, through their protein component histones, directly activate T cells and specifically enhance Th17 cell differentiation. This modulatory role of neutrophils, NETs and their histones is mediated downstream of TLR2 in T cells, resulting in phosphorylation of STAT3. The innate stimulation of a specific adaptive immune cell subset provides an additional mechanism demonstrating a direct link between neutrophils, NETs and T cell autoimmunity.
Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are ...gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer ...initiation. Genetic loss of Gclm prevents a tumor’s ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
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•The GSH antioxidant pathway is required for cancer initiation•After cancer initiation, GSH is dispensable due to alternative antioxidant pathways•The TXN antioxidant pathway is upregulated in tumors•Inhibition of both GSH and TXN pathways causes synergistic cancer cell death
Harris et al. show that the antioxidant glutathione (GSH) is required for cancer initiation but not for established tumors partly due to upregulation of the thioredoxin (TXN) antioxidant pathway in the latter. Consequently, blocking both GSH and TXN pathways synergistically inhibits tumor growth.
Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells ...that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4 ⁺ T-cell population that is stimulated by norepinephrine to release ACh, ChAT ⁺ B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT ⁺ B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT ⁺ B cells controlling the local recruitment of neutrophils.
Follicular T-helper (TFH) cells cooperate with GL7+CD95+ germinal center (GC) B cells to induce antibody maturation. Herein, we identify the transcription factor IRF4 as a T-cell intrinsic ...precondition for TFH cell differentiation and GC formation. After immunization with protein or infection with the protozoon Leishmania major, draining lymph nodes (LNs) of IFN-regulatory factor-4 (Irf4–/–) mice lacked GCs and GC B cells despite developing normal initial hyperplasia. GCs were also absent in Peyer’s patches of naive Irf4–/– mice. Accordingly, CD4+ T cells within the LNs and Peyer’s patches failed to express the TFH key transcription factor B-cell lymphoma-6 and other TFH-related molecules. During chronic leishmaniasis, the draining Irf4–/– LNs disappeared because of massive cell death. Adoptive transfer of WT CD4+ T cells or few L. major primed WT TFH cells reconstituted GC formation, GC B-cell differentiation, and LN cell survival. In support of a T-cell intrinsic IRF4 activity, Irf4–/– TFH cell differentiation was not rescued by close neighborhood to transferred WT TFH cells. Together with its known B lineage-specific roles during plasma cell maturation and class switch, our study places IRF4 in the center of antibody production toward T-cell–dependent antigens.
Differentiation of murine T-helper (Th) 17 cells is induced by antigenic stimulation and the sequential action of the cytokines IL-6, IL-21, and IL-23, along with TGFβ. Current dogma proposes that ...IL-6 induces IL-21, which, in a STAT3-dependent manner, amplifies its own transcription, contributes to IL-17 production, and, moreover, promotes the expression of the IL-23 receptor. This, in turn, prepares cells for IL-23-mediated stabilization of the Th17 phenotype. Here we demonstrate that these effects of IL-21 on Th17 differentiation are completely dependent on IFN regulatory factor 4 (IRF4). After culturing in the presence of IL-21 plus TGFβ, IRF4-deficient (Irf4⁻/⁻) Th cells showed a profound intrinsic defect in IL-17 production and in the autocrine IL-21 loop. Likewise, the levels of IL-23 receptor and the lineage-specific orphan nuclear receptors RORα and RORγt were diminished, whereas the T regulatory (Treg) transcription factor forkhead box P3 (Foxp3) was strongly up-regulated, consistent with the reciprocal relationship between Th17 and Treg development. Despite this loss of IL-21 functions, IL-21-induced STAT3 activation was unimpaired and induced normal Socs3 expression. Forced expression of Foxp3 in WT cells inhibited IL-21-mediated IL-17 production, suggesting that the increase in Foxp3 contributes to the Irf4⁻/⁻ phenotype. Additionally, the low levels of RORα and RORγt are also partially responsible, because simultaneous overexpression of both proteins restored IL-17 production in Irf4⁻/⁻ cells to some extent. These data highlight IRF4 as a decisive factor during the IL-21-mediated steps of Th17 development by influencing the balance of Foxp3, RORα, and RORγt.
Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being ...fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesions.
Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that ...virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3–/–, E4BP4–/–) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.
Abstract
Background
Multiple sclerosis
(MS) is a neurological condition whose symptoms, severity, and progression over time vary enormously among individuals. Ideally, each person living with MS ...should be provided with an accurate prognosis at the time of diagnosis, precision in initial and subsequent treatment decisions, and improved timeliness in detecting the need to reassess treatment regimens. To manage these three components, discovering an accurate, objective measure of overall disease severity is essential.
Machine learning
(ML) algorithms can contribute to finding such a clinically useful biomarker of MS through their ability to search and analyze datasets about potential biomarkers at scale. Our aim was to conduct a systematic review to determine how, and in what way, ML has been applied to the study of MS biomarkers on data from sources other than magnetic resonance imaging.
Methods
Systematic searches through eight databases were conducted for literature published in 2014–2020 on MS and specified ML algorithms.
Results
Of the 1, 052 returned papers, 66 met the inclusion criteria. All included papers addressed developing classifiers for MS identification or measuring its progression, typically, using hold-out evaluation on subsets of fewer than 200 participants with MS. These classifiers focused on biomarkers of MS, ranging from those derived from omics and phenotypical data (34.5% clinical, 33.3% biological, 23.0% physiological, and 9.2% drug response). Algorithmic choices were dependent on both the amount of data available for supervised ML (91.5%; 49.2% classification and 42.3% regression) and the requirement to be able to justify the resulting decision-making principles in healthcare settings. Therefore, algorithms based on decision trees and support vector machines were commonly used, and the maximum average performance of 89.9% AUC was found in random forests comparing with other ML algorithms.
Conclusions
ML is applicable to determining how candidate biomarkers perform in the assessment of disease severity. However, applying ML research to develop decision aids to help clinicians optimize treatment strategies and analyze treatment responses in individual patients calls for creating appropriate data resources and shared experimental protocols. They should target proceeding from segregated classification of signals or natural language to both holistic analyses across data modalities and clinically-meaningful differentiation of disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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