Reference Ranges of Ventricular Morphology and Function in Healthy Chinese Adults: A Multicenter 3 T MRI Study.

BACKGROUND: Magnetic resonance imaging (MRI) reference ranges for ventricular morphology and function in the Chinese population are lacking. PURPOSE: To establish the MRI reference ranges of left and right ventricular (LV and RV) morphology and function based on a large multicenter cohort. STUDY TYPE: Prospective. POPULATION: One thousand and twelve healthy Chinese Han adults. FIELD STRENGTH/SEQUENCE: Balanced steady-state free procession cine sequence at 3.0 T. ASSESSMENT: Biventricular end-diastolic, end-systolic, stroke volume, and ejection fraction (EDV, ESV, SV, and EF), LV mass (LVM), end-diastolic and end-systolic dimension (LVEDD and LVESD), anteroseptal wall thickness (AS), and posterolateral wall thickness (PL) were measured. Body surface area (BSA) and height were used to index biventricular parameters. Parameters were compared between age groups and sex. STATISTICAL TESTS: Independent-samples t-tests or Mann-Whitney U test to compare mean values between sexes; ANOVA or Kruskal-Wallis test to compare mean values among age groups; linear regression to assess the relationships between cardiac parameters and age (correlation coefficient, r). A P value <0.05 was considered statistically significant. RESULTS: The biventricular volumes, LVM, LVEDD, RVEDV/LVEDV ratio, LVESD, AS, and PL were significantly greater in males than in females, even after indexing to BSA or height, while LVEF and RVEF were significantly lower in males than in females. For both sexes, age was significantly negatively correlated with biventricular volumes (male and female: LVEDV [r = -0.491; r = -0.373], LVESV [r = -0.194; r = -0.184], RVEDV [r = -0.639; r = -0.506], RVESV [r = -0.270; r = -0.223]), with similar correlations after BSA normalization. LVEF (r = 0.043) and RVEF (r = 0.033) showed a significant correlation with age in females, but not in males (P = 0.889; P = 0.282). DATA CONCLUSION: MRI reference ranges for biventricular morphology and function in Chinese adults are presented and show significant associations with age and sex. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Electrolysis Synthesis of Carbides and Carbon Dioxide Capture in Molten Salts.

The application of carbides in catalysis, batteries, aerospace fields, etc. has been continuously expanded and deepened, which is attributed to the diversified physicochemical properties of carbides via a tune-up of their morphology, composition, and microstructure. The emergence of MAX phases and high entropy carbides with unparalleled application potential undoubtedly further stimulates the research upsurge of carbides. The traditional pyrometallurgical or hydrometallurgical synthesis of carbides inevitably faces the shortcomings of complex process, unacceptable energy consumption, extreme environmental pollution, and beyond. The molten salt electrolysis synthesis method with the superiorities of straightforward route, high efficiency, and environmental friendliness has demonstrated its validity in the synthesis of various carbides, which naturally initiates more research. In particular, the process can achieve CO2 capture while synthesizing carbides based on the excellent CO2 capture capability of some molten salts, which is of great significance for carbon neutralization. In this paper, the synthesis mechanism of carbide by molten salt electrolysis, the process of CO2 capture and carbides conversion, the latest research progress in the synthesis of binary, ternary, multi-component, and composite carbides are reviewed. Finally, the challenges, development perspectives, and research directions of electrolysis synthesis of carbides in molten salts are featured.

NAC1 confines virus-specific memory formation of CD4+ T cells through the ROCK1-mediated pathway.

Nucleus accumbens-associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8+ T cells, and antitumor immunity, but little is known about its effects on T-cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4+ T cells during viral infection. Analysis of CD4+ T cells from wild-type (WT) and NAC1-deficient (-/- ) mice showed that NAC1 is essential for T-cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4+ T-cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates glycolysis and correlates with the AMPK-mTOR pathway and causes autophagy defective in CD4+ T cells. Loss of NAC1 reduced the expression of ROCK1 and the phosphorylation and stabilization of BECLIN1. However, a forced expression of ROCK1 in NAC1-/- CD4+ T cells restored autophagy and the activity of the AMPK-mTOR pathway. In animal experiments, adoptively transferred NAC1-/- CD4+ T cells or NAC1-/- mice challenged with VACV showed enhanced formation of VACV-specific CD4+ memory T cells compared to adoptively transferred WT CD4+ T cells or WT mice. This memory T-cell formation enhancement was abrogated by forcing expression of ROCK1. Our study reveals a novel role for NAC1 as a suppressor of CD4+ T-cell memory formation and suggests that targeting NAC1 could be a new approach to promoting memory CD4+ T-cell development, which is critical for an effective immune response against pathogens.

Reference ranges of myocardial T1 and T2 mapping in healthy Chinese adults: a multicenter 3T cardiovascular magnetic resonance study.

BACKGROUND: Although reference ranges of T1 and T2 mapping are well established for cardiovascular magnetic resonance (CMR) at 1.5T, data for 3T are still lacking. The objective of this study is to establish reference ranges of myocardial T1 and T2 based on a large multicenter cohort of healthy Chinese adults at 3T CMR. METHODS: A total of 1015 healthy Chinese adults (515 men, age range: 19-87 years) from 11 medical centers who underwent CMR using 3T Siemens scanners were prospectively enrolled. T1 mapping was performed with a motion-corrected modified Look-Locker inversion recovery sequence using a 5(3)3 scheme. T2 mapping images were acquired using T2-prepared fast low-angle shot sequence. T1 and T2 relaxation times were quantified for each slice and each myocardial segment. The T1 mapping and extracellular volume standardization (T1MES) phantom was used for quality assurance at each center prior to subject scanning. RESULTS: The phantom analysis showed strong consistency of spin echo, T1 mapping, and T2 mapping among centers. In the entire cohort, global T1 and T2 reference values were 1193 ± 34 ms and 36 ± 2.5 ms. Global T1 and T2 values were higher in females than in males (T1: 1211 ± 29 ms vs. 1176 ± 30 ms, p < 0.001; T2: 37 ± 2.3 ms vs. 35 ± 2.5 ms, p < 0.001). There were statistical differences in global T2 across age groups (p < 0.001), but not in global T1. Linear regression showed no correlation between age and global T1 or T2 values. In males, positive correlation was found between heart rate and global T1 (r = 0.479, p < 0.001). CONCLUSIONS: Using phantom-validated imaging sequences, we provide reference ranges for myocardial T1 and T2 values on 3T scanners in healthy Chinese adults, which can be applied across participating sites. Trial registration URL: http://www.chictr.org.cn/index.aspx . Unique identifier: ChiCTR1900025518. Registration name: 3T magnetic resonance myocardial quantitative imaging standardization and reference value study: a multi-center clinical study.

Chicken-derived CD20 antibodies with potent B-cell depletion activity.

We report four novel anti-human CD20 (hCD20) monoclonal antibodies (mAbs) discovered from a phylogenetically distant species-chickens. The chicken-human chimaeric antibodies exhibit at least 10-fold enhanced antibody-dependent cellular cytotoxicity (ADCC) and 4-8-fold stronger complement-dependent cytotoxicity (CDC) relative to the clinically used mouse-human chimaeric anti-hCD20 antibody rituximab (RTX). Thus, to our knowledge these mAbs are the first to significantly outperform RTX in both Fc-mediated mechanisms of action. The antibodies show 20-100-fold superior depletion of B cells in whole blood from healthy humans relative to RTX and retain efficacy in vivo. One of the mAbs, AC1, can bind mouse CD20, indicating specificity for a novel hCD20 epitope inaccessible to current (mouse-derived) anti-hCD20 mAbs. A humanized version of one antibody, hAC11-10, was created by complementarity-determining region (CDR) grafting into a human variable region framework and this molecule retained the ADCC, in vitro human whole-blood B-cell depletion, and in vivo lymphoma cell depletion activities of the parent. These mAbs represent promising monotherapy candidates for improving upon current less-than-ideal clinical outcomes in lymphoid malignancies and provide an arsenal of biologically relevant molecules for the development of next-generation CD20-mediated immunotherapies including bispecific T-cell engagers (BiTE), antibody-drug conjugates (ADC) and chimaeric antigen receptor-engineered T (CAR-T) cells.

Triple quantitative detection of three inflammatory biomarkers with a biotin-streptavidin-phycoerythrin based lateral flow immunoassay.

Quantified inflammatory biomarkers are effective clinical strategy for correct and reasonable drug treatment. In the study, a triple lateral flow immunoassay (triple LFIA) had firstly been developed for specific and simultaneous detection of three pivotal inflammatory biomarkers (PCT, CRP and SAA) via biotin-streptavidin-phycoerythrin signal amplification system in one strip. The developed triple LFIA adopted phycoerythrin (PE) as chromophore to eliminate auto-fluorescence interference from plasma biomolecules and anti-PE mAb as single control line to reduce the nonspecific adsorption, which featured particular advantages in high sensitivity and specificity in a large range of analyte concentrations with the LODs of 0.106 ng/mL for PCT, 0.345 µg/mL for CRP and 3.112 µg/mL SAA, respectively. And the linear quantitative detection ranges were from 0.106 to 100 ng/mL, from 0.345 to 200 µg/mL, and from 3.112 to 200 µg/mL, respectively. Compared to commercial chemiluminescence immunoassay method, the correlations for tested PCT, CRP and SAA in 108 clinical samples were 0.989, 0.987 and 0.988, respectively. In summary, we had proposed a rapid and accurate plasma detection to measure inflammation factors, which facilitated the clinical value to achieve precise treatment.

Autophagy in T-cell differentiation, survival and memory.

Over the past decade, autophagy has emerged as a critical regulatory mechanism of the immune system through critically controlling various aspects of T cell biology and determining the fate of different T cell subsets. Autophagy maintains T cell development and survival by regulating the degradation of organelles and apoptotic proteins. The autophagic process also impacts the formation of memory T cells. Alteration of autophagy in T cells may lead to a variety of pathological conditions such as inflammation, autoimmune diseases and cancer. In this review, we discuss how autophagy impacts T cell differentiation, survival and memory, and its implication in immunotherapy for various diseases.

A first-principles study on the electronic and optical properties of a type-II C2N/g-ZnO van der Waals heterostructure.

The structural, electronic and optical properties of a new van der Waals heterostructure, C2N/g-ZnO, composed of C2N and g-ZnO monolayers with an intrinsic type-II band alignment and a direct bandgap of 0.89 eV at the Γ point, are extensively studied using first-principles density functional theory calculations. The results indicate that the special optoelectronic properties of the constructed heterostructure mainly originate from the interlayer coupling and electron transfer between the C2N and g-ZnO monolayers, and the photogenerated electrons and holes are located on the C2N and g-ZnO layers, respectively, which reduces the recombination probability of the electron-hole pairs. According to Bader charge analysis, there are 0.029 electrons transferred from g-ZnO to C2N to form a built-in electric field of ∼9.5 eV at the interface. Furthermore, the tunability of the electronic properties of the C2N/g-ZnO heterostructure under vertical strain and electric field is explored. Under different strains, the type-II band alignment properties of the heterostructure are retained and the vertical compressive strain has a greater influence on the bandgap modulation than the vertical stretching strain. The implemented electric field also does not change the type-II band alignment but changes the bandgap of the heterostructure from 1.30 to 0.58 eV when the electric field strength varies from -0.6 to 0.6 V Å-1. In addition, the absorption spectrum of the C2N/g-ZnO heterostructure under solar light is also studied. The absorption range of the heterostructure varies from the ultraviolet to near-infrared region with the absorption intensity in the order of 105 cm-1. All of these studies indicate that the C2N/g-ZnO heterostructure has excellent electronic and optical properties and promising applications in nanoelectronics and optoelectronics.

Quantitative and Qualitative Analysis of Atherosclerotic Stenosis in the Middle Cerebral Artery Using High-Resolution Magnetic Resonance Imaging.

PURPOSE: We analyzed and compared the imaging characteristics of the vessel wall of the middle cerebral artery (MCA) in symptomatic and asymptomatic patients using a 3.0-T high-resolution magnetic resonance imaging (HR-MRI) protocol, including a 3-dimensional T1-sampling perfection with application-optimized contrasts using different flip angle evolutions sequence. METHODS: Fifty-three patients with atherosclerotic stenosis of the MCA underwent 3.0-T HR-MRI examinations. The characteristics of atherosclerotic plaques in 53 patients (28 symptomatic, 25 asymptomatic) were analyzed, including plaque distribution and signal intensity. Plaque burden (PB), stenosis degree, and the remodeling index were measured and compared between symptomatic and asymptomatic patients. RESULTS: The PB of the symptomatic group was significantly higher than that of the asymptomatic group (P = .006), and moderate-severe stenosis was more common (P = .01). The remodeling index of the symptomatic group was also lower (P = .015) and negative remodeling (NR) was more common (P = .043). Binary logistic regression analysis showed that stenosis degree was a risk factor in symptomatic patients (odds ratio = 135, P = .023). CONCLUSION: There is a trend that some characteristics of plaques and vessels, including the moderate-severe stenosis, larger PB, and NR, were observed more frequently among patients with symptomatic atherosclerotic stenosis of the MCA than among asymptomatic patients.

Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents.

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer resistant to traditional treatments, although a limited number of early-stage patients can undergo radical resection. Immunotherapies for the treatment of haematological malignancies as well as solid tumours have been substantially improved over the past decades, and impressive results have been obtained in recent preclinical and clinical trials. However, PDAC is likely the exception because of its unique tumour microenvironment (TME). In this review, we summarize the characteristics of the PDAC TME and focus on the network of various tumour-infiltrating immune cells, outlining the current advances in PDAC immunotherapy and addressing the effect of the PDAC TME on immunotherapy. This review further explores the combinations of different therapies used to enhance antitumour efficacy or reverse immunodeficiencies and describes optimizable immunotherapeutic strategies for PDAC. The concordant combination of various treatments, such as targeting cancer cells and the stroma, reversing suppressive immune reactions and enhancing antitumour reactivity, may be the most promising approach for the treatment of PDAC. Traditional treatments, especially chemotherapy, may also be optimized for individual patients to remodel the immunosuppressive microenvironment for enhanced therapy.

The TNF Superfamily Molecule LIGHT Promotes the Generation of Circulating and Lung-Resident Memory CD8 T Cells following an Acute Respiratory Virus Infection.

The transition of effector T cells or memory precursors into distinct long-lived memory T cell subsets is not well understood. Although many molecules made by APCs can contribute to clonal expansion and effector cell differentiation, it is not clear if clonal contraction and memory development is passive or active. Using respiratory virus infection, we found that CD8 T cells that cannot express the TNF family molecule lymphotoxin-like, exhibits inducible expression, competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes (LIGHT) are unimpaired in their initial response and clonally expand to form effector cell pools. Thereafter, LIGHT-deficient CD8 T cells undergo strikingly enhanced clonal contraction with resultant compromised accumulation of both circulating and tissue-resident memory cells. LIGHT expression at the peak of the effector response regulates the balance of several pro- and antiapoptotic genes, including Akt, and has a preferential impact on the development of the peripheral memory population. These results underscore the importance of LIGHT activity in programming memory CD8 T cell development, and suggest that CD8 effector T cells can dictate their own fate into becoming memory cells by expressing LIGHT.

USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development.

The NAD-dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis. We have identified a ubiquitin-specific peptidase, USP22, one of the 11 death-from-cancer signature genes that are critical in controlling cell growth and death, as a positive regulator of Sirt1. USP22 interacts with and stabilizes Sirt1 by removing polyubiquitin chains conjugated onto Sirt1. The USP22-mediated stabilization of Sirt1 leads to decreasing levels of p53 acetylation and suppression of p53-mediated functions. In contrast, depletion of endogenous USP22 by RNA interference destabilizes Sirt1, inhibits Sirt1-mediated deacetylation of p53 and elevates p53-dependent apoptosis. Genetic deletion of the usp22 gene results in Sirt1 instability, elevated p53 transcriptional activity and early embryonic lethality in mice. Our study elucidates a molecular mechanism in suppression of cell apoptosis by stabilizing Sirt1 in response to DNA damage and reveals a critical physiological function of USP22 in mouse embryonic development.

The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice.

Humoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Herein, we probed the role of the endoplasmic reticulum-associated, stress-activated E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1) in B cell differentiation. Using mice with a specific Hrd1 deletion in pro-B cells and subsequent B cell developmental stages, we showed that the E3 ubiquitin ligase Hrd1 governs a critical checkpoint during B cell development. We observed that Hrd1 is required for degradation of the pre-BCR complex during the early stage of B cell development. As a consequence, loss of Hrd1 in the B cell lineage resulted in increased pre-BCR expression levels and a developmental defect in the transition from large to small pre-B cells. This defect, in turn, resulted in reduced fewer mature B cells in bone marrow and peripheral lymphoid organs. Our results revealed a novel critical role of Hrd1 in controlling a critical checkpoint in B cell-mediated immunity and suggest that Hrd1 may functioning as an E3 ubiquitin ligase of the pre-BCR complex.

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors.

Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare NETs originating from the liver. These tumors are associated with heterogeneous prognosis, and few treatment targets for PHNETs have been identified. Because the major genetic alterations in PHNET are still largely unknown, we performed whole-exome sequencing of 22 paired tissues from PHNET patients and identified 22 recurring mutations of somatic genes involved in the following activities: epigenetic modification (BPTF, MECP2 and WDR5), cell cycle (TP53, ATM, MED12, DIDO1 and ATAD5) and neural development (UBR4, MEN1, GLUL and GIGYF2). Here, we show that TP53 and the SET domain containing the 1B gene (SETD1B) are the most frequently mutated genes in this set of samples (3/22 subjects, 13.6%). A biological analysis suggests that one of the three SETD1B mutants, A1054del, promotes cell proliferation, migration and invasion compared to wild-type SETD1B. Our work unveils that SETD1B A1054del mutant is functional in PHNET and implicates genes including TP53 in the disease. Our findings thus characterize the mutational landscapes of PHNET and implicate novel gene mutations linked to PHNET pathogenesis and potential therapeutic targets.

Targeting Stem Cell-Derived Tissue-Associated Regulatory T Cells for Type 1 Diabetes Immunotherapy.

PURPOSE OF REVIEW: Type 1 diabetes (T1D) is an autoimmune disease in which the immune cells selectively destroy the pancreatic beta (ß) cells and results in the deficiency of insulin production. The optimal treatment strategy for T1D should be preventing of ß-cell destruction in the pancreas. The purpose of this review is to discuss the immunological therapeutic mechanisms that will help to understand the development and control of ß-cell destruction. The review also presents a novel method for development of autoantigen (Ag)-specific regulatory T cells (Tregs) for T1D immunotherapy. RECENT FINDINGS: Pancreatic-resident Tregs have the ability to dramatically suppress hyperactive immune cells. Islet cell transplantation is another attractive approach to replace the failed ß cells. Due to the limited source of islet cells, research is going on in the use of animal cells and adult stem cells that may be derived from the patient's own body to produce ß cells for transplantation. The mechanism behind the pancreatic ß-cell destruction is largely unknown. In this review, a novel approach for the generation of tissue-associated Tregs from stem cells is considered. The stem cell-derived tissue-associated Tregs have the ability to home to the damaged pancreas to prevent the destruction. The review also provides new insights on the mechanism on how these suppressive immune cells protect the pancreas from the destruction of autoimmune cells. A novel method to develop functional auto Ag-specific Tregs that are derived from induced pluripotent stem cells (iPSCs), i.e., iPSC-Tregs, is discussed. Adoptive transfer of the iPSC-Tregs can substantially suppress T1D development in a murine model.

HVEM Imprints Memory Potential on Effector CD8 T Cells Required for Protective Mucosal Immunity.

Mucosal immunity to reinfection with a highly virulent virus requires the accumulation and persistence of memory CD8 T cells at the site of primary infection. These cells may derive from memory precursor effector cells (MPECs), which are distinct from short-lived effector cells that provide acute protection but are often destined to die. Using respiratory virus infection, we show that herpes virus entry mediator (HVEM; TNFRSF14), a member of the TNF receptor superfamily, provides key signals for MPEC persistence. HVEM-deficient CD8 T cells expanded normally but were skewed away from MPECs with resultant poor development of circulating and lung-resident memory cells. HVEM was selectively expressed on MPECs whereas MPECs deficient in HVEM failed to survive in adoptive transfer recipients. As a consequence, HVEM-deficient recipients failed to afford protection against respiratory reinfection with influenza virus. HVEM therefore represents a critical signal for MPECs and development of protective mucosal CD8 T cell memory.

The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation.

Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed-protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation. Loss of Gcn5 functions impaired T cell proliferation, IL-2 production, and Th1/Th17, but not Th2 and regulatory T cell differentiation. Gcn5 is recruited onto the il-2 promoter by interacting with the NFAT in T cells upon TCR stimulation. Interestingly, instead of directly acetylating NFAT, Gcn5 catalyzes histone H3 lysine H9 acetylation to promote IL-2 production. T cell-specific suppression of Gcn5 partially protected mice from myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, an experimental model for human multiple sclerosis. Our study reveals previously unknown physiological functions for Gcn5 and a molecular mechanism underlying these functions in regulating T cell immunity. Hence Gcn5 may be an important new target for autoimmune disease therapy.

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas.

Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity.

TGF-ß-Induced Regulatory T Cells Directly Suppress B Cell Responses through a Noncytotoxic Mechanism.

Foxp3(+) regulatory T cells (Treg) playing a crucial role in the maintenance of immune tolerance and prevention of autoimmune diseases consist of thymus-derived naturally occurring CD4(+)Foxp3(+) Treg cells (nTreg) and those that can be induced ex vivo with TGF-ß (iTreg). Although both Treg subsets share similar phenotypes and functional characteristics, they also have potential biologic differences on their biology. The role of iTreg in regulating B cells remains unclear so far. The suppression assays of Treg subsets on activation, proliferation, and Abs production of B cells were measured using a Treg and B cell coculture system in vitro. Transwell and Ab blockade experiments were performed to assess the roles of cell contact and soluble cytokines. Treg were adoptively transferred to lupus mice to assess in vivo effects on B cells. Like nTreg, iTreg subset also directly suppressed activation and proliferation of B cells. nTreg subset suppressed B cell responses through cytotoxic manner related to expression of granzyme A, granzyme B, and perforin, whereas the role of iTreg subset on B cells did not involve in cytotoxic action but depending on TGF-ß signaling. Furthermore, iTreg subset can significantly suppress Ab produced by lupus B cells in vitro. Comparison experiments using autoantibodies microarrays demonstrated that adoptive transfer of iTreg had a superior effect than nTreg subset on suppressing lupus B cell responses in vivo. Our data implicate a role and advantage of iTreg subset in treating B cell-mediated autoimmune diseases, boosting the translational potential of these findings.