Redefining thymus medulla specialization for central tolerance

During αβT cell development, the thymus medulla represents an essential microenvironment for T cell tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3+ T-regulatory cell (T-reg) development. Here, by performing TEC-specific deletion of the thymus medulla regulator lymphotoxin β receptor (LTβR), we show that thymic tolerance mechanisms operate independently of LTβR-mediated mTEC development and organization. Consistent with this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and support T-reg development despite loss of LTβR-mediated medulla organogenesis. Moreover, we demonstrate that LTβR controls thymic tolerance by regulating the frequency and makeup of intrathymic dendritic cells (DCs) required for effective thymocyte negative selection. In all, our study demonstrates that thymus medulla specialization for thymic tolerance segregates from medulla organogenesis and instead involves LTβR-mediated regulation of the thymic DC pool.</jats:p

Transcriptional profiles of non-neuronal and immune cells in mouse trigeminal ganglia

Non-neuronal cells constitute 90%–95% of sensory ganglia. These cells, especially glial and immune cells, play critical roles in the modulation of sensory neurons. This study aimed to identify, profile, and summarize the types of trigeminal ganglion (TG) non-neuronal cells in naïve male mice using published and our own data generated by single-cell RNA sequencing, flow cytometry, and immunohistochemistry. TG has five types of non-neuronal cells, namely, glial, fibroblasts, smooth muscle, endothelial, and immune cells. There is an agreement among publications for glial, fibroblasts, smooth muscle, and endothelial cells. Based on gene profiles, glial cells were classified as myelinated and non-myelinated Schwann cells and satellite glial cells. Mpz has dominant expression in Schwann cells, and Fabp7 is specific for SCG. Two types of Col1a2+ fibroblasts located throughout TG were distinguished. TG smooth muscle and endothelial cells in the blood vessels were detected using well-defined markers. Our study reported three types of macrophages (Mph) and four types of neutrophils (Neu) in TG. Mph were located in the neuronal bodies and nerve fibers and were sub-grouped by unique transcriptomic profiles with Ccr2, Cx3cr1, and Iba1 as markers. A comparison of databases showed that type 1 Mph is similar to choroid plexus-low (CPlo) border-associated Mph (BAMs). Type 2 Mph has the highest prediction score with CPhi BAMs, while type 3 Mph is distinct. S100a8+ Neu were located in the dura surrounding TG and were sub-grouped by clustering and expressions of Csf3r, Ly6G, Ngp, Elane, and Mpo. Integrative analysis of published datasets indicated that Neu-1, Neu-2, and Neu-3 are similar to the brain Neu-1 group, while Neu-4 has a resemblance to the monocyte-derived cells. Overall, the generated and summarized datasets on non-neuronal TG cells showed a unique composition of myeloid cell types in TG and could provide essential and fundamental information for studies on cell plasticity, interactomic networks between neurons and non-neuronal cells, and function during a variety of pain conditions in the head and neck regions

Metabolic Activation of Intrahepatic CD8+ T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with Hepatocytes

SummaryHepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8+ T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8+ T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8+ and NKT cells cooperatively induce liver damage. Hepatocellular LTβR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development

Efficiency of Finding Muon Track Trigger Primitives in CMS Cathode Strip Chambers

In the CMS Experiment, muon detection in the forward direction is accomplished by cathode strip chambers~(CSC). These detectors identify muons, provide a fast muon trigger, and give a precise measurement of the muon trajectory. There are 468 six-plane CSCs in the system. The efficiency of finding muon trigger primitives (muon track segments) was studied using~36 CMS CSCs and cosmic ray muons during the Magnet Test and Cosmic Challenge~(MTCC) exercise conducted by the~CMS experiment in~2006. In contrast to earlier studies that used muon beams to illuminate a very small chamber area ($< \! 0.01$~m$^2$), results presented in this paper were obtained by many installed CSCs operating {\em in situ} over an area of $\approx \! 23$~m$^2$ as a part of the~CMS experiment. The efficiency of finding 2-dimensional trigger primitives within 6-layer chambers was found to be~$99.93 \pm 0.03\%$. These segments, found by the CSC electronics within $800$~ns after the passing of a muon through the chambers, are the input information for the Level-1 muon trigger and, also, are a necessary condition for chambers to be read out by the Data Acquisition System

Innate Lymphoid Cell Plasticity in Mucosal Infections

Mucosal tissue homeostasis is a dynamic process that involves multiple mechanisms including regulation of innate lymphoid cells (ILCs). ILCs are mostly tissue-resident cells which are critical for tissue homeostasis and immune response against pathogens. ILCs can sense environmental changes and rapidly respond by producing effector cytokines to limit pathogen spread and initiate tissue recovery. However, dysregulation of ILCs can also lead to immunopathology. Accumulating evidence suggests that ILCs are dynamic population that can change their phenotype and functions under rapidly changing tissue microenvironment. However, the significance of ILC plasticity in response to pathogens remains poorly understood. Therefore, in this review, we discuss recent advances in understanding the mechanisms regulating ILC plasticity in response to intestinal, respiratory and genital tract pathogens. Key transcription factors and lineage-guiding cytokines regulate this plasticity. Additionally, we discuss the emerging data on the role of tissue microenvironment, gut microbiota, and hypoxia in ILC plasticity in response to mucosal pathogens. The identification of new pathways and molecular mechanisms that control functions and plasticity of ILCs could uncover more specific and effective therapeutic targets for infectious and autoimmune diseases where ILCs become dysregulated

Nanoreactors Based On Dnazyme-Functionalized Magnetic Nanoparticles Activated By Magnetic Field

A new biomimetic nanoreactor design, MaBiDz, is presented based on a copolymer brush in combination with superparamagnetic nanoparticles. This cellular nanoreactor features two species of magnetic particles, each functionalized with two components of a binary deoxyribozyme system. In the presence of a target mRNA analyte and a magnetic field, the nanoreactor is assembled to form a biocompartment enclosed by the polymeric brush that enables catalytic function of the binary deoxyribozyme with enhanced kinetics. MaBiDz was demonstrated here as a cellular sensor for rapid detection and imaging of a target mRNA biomarker for metastatic breast cancer, and its function shows potential to be expanded as a biomimetic organelle that can downregulate the activity of a target mRNA biomarker

Magnetic Field-Activated Sensing Of Mrna In Living Cells

Detection of specific mRNA in living cells has attracted significant attention in the past decade. Probes that can be easily delivered into cells and activated at the desired time can contribute to understanding translation, trafficking and degradation of mRNA. Here we report a new strategy termed magnetic field-activated binary deoxyribozyme (MaBiDZ) sensor that enables both efficient delivery and temporal control of mRNA sensing by magnetic field. MaBiDZ uses two species of magnetic beads conjugated with different components of a multicomponent deoxyribozyme (DZ) sensor. The DZ sensor is activated only in the presence of a specific target mRNA and when a magnetic field is applied. Here we demonstrate that MaBiDZ sensor can be internalized in live MCF-7 breast cancer cells and activated by a magnetic field to fluorescently report the presence of specific mRNA, which are cancer biomarkers