B-cell-derived IL-10 promotes allergic sensitization in asthma regulated by Bcl-3

Aeroallergen sensitization,mainly mediated by lung epithelium and dendritic cells(DCs),is integral to allergic asthma pathogenesis and progression.IL-10 has a dual role in immune responses,as it inhibits myeloid cell activation but promotes B-cell responses and epithelial cell proliferation.Here,we report a proinflammatory function of B-cell-derived IL-10 modulated by Bcl-3 in allergic asthma.Specifically,Bcl-3^(−/−)mice showed elevated IL-10 levels and were found to be highly vulnerable to allergic asthma induced by house dust mites(HDMs).IL-10 had a positive correlation with the levels of the DC chemoattractant CCL-20 in HDM-sensitized mice and in patients with asthma and induced a selective increase in CCL-20 production by mouse lung epithelial cells.Blockade of IL-10 or IL-10 receptors during sensitization dampened both HDM-induced sensitization and asthma development.IL-10 levels peaked 4 h post sensitization with HDM and IL-10 was primarily produced by B cells under Bcl-3–Blimp-1–Bcl-6 regulation.Mice lacking B-cell-derived IL-10 displayed decreased lung epithelial CCL-20 production and diminished DC recruitment to the lungs upon HDM sensitization,thereby demonstrating resistance to HDM-induced asthma.Moreover,responses to HDM stimulation in Bcl-3^(−/−)mice lacking B-cell-derived IL-10 were comparable to those in Bcl-3^(+/+)mice.The results revealed an unexpected role of B-cell-derived IL-10 in promoting allergic sensitization and demonstrated that Bcl-3 prevents HDM-induced asthma by inhibiting B-cell-derived IL-10 production.Thus,targeting the Bcl-3/IL-10 axis to inhibit allergic sensitization is a promising approach for treating allergic asthma.

Immune‑Ageing Evaluation of Peripheral T and NK Lymphocyte Subsets in Chinese Healthy Adults

Ageing is often accompanied with a decline in immune system function,resulting in immune ageing.Numerous studies have focussed on the changes in different lymphocyte subsets in diseases and immunosenescence.The change in immune phenotype is a key indication of the diseased or healthy status.However,the changes in lymphocyte number and phenotype brought about by ageing have not been comprehensively analysed.Here,we analysed T and natural killer(NK)cell subsets,the phenotype and cell differentiation states in 43,096 healthy individuals,aged 20–88 years,without known diseases.Thirty-six immune parameters were analysed and the reference ranges of these subsets were established in different age groups divided into 5-year intervals.The data were subjected to random forest machine learning for immune-ageing modelling and confirmed using the neural network analysis.Our initial analysis and machine modelling prediction showed that na.ve T cells decreased with ageing,whereas central memory T cells(Tcm)and effector memory T cells(Tem)increased cluster of differentiation(CD)28-associated T cells.This is the largest study to investigate the correlation between age and immune cell function in a Chinese population,and provides insightful differences,suggesting that healthy adults might be considerably influenced by age and sex.The age of a person's immune system might be different from their chronological age.Our immune-ageing modelling study is one of the largest studies to provide insights into‘immune-age’rather than‘biological-age’.Through machine learning,we identified immune factors influencing the most through ageing and built a model for immune-ageing prediction.Our research not only reveals the impact of age on immune parameter differences within the Chinese population,but also provides new insights for monitoring and preventing some diseases in clinical practice.

Aureane-type sesquiterpene tetraketides as a novel class of immunomodulators with interleukin-17A inhibitory activity

Interleukin(IL)-17A,a pro-inflammatory cytokine,is a fundamental function in the onset and advancement of multiple immune diseases.To uncover the primary compounds with IL-17A inhibitory activity,a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions.Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus,Myrothecium gramineum,showed remarkable IL-17A inhibitory activity.Nine new aureane-type sesquiterpene tetraketides,myrogramins A-I(1,4-11),and two known ones(2 and 3)were isolated and identified from the strain.Compounds 1,3,4,10,and 11 exhibited significant IL-17A inhibitory activity.Among them,compound 3,with a high fermentation yield dosedependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions.Strikingly,compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension.Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity,and hold great promise applications in treating IL-17A-mediated immune diseases.

γδT cells:origin and fate,subsets,diseases and immunotherapy

The intricacy of diseases,shaped by intrinsic processes like immune system exhaustion and hyperactivation,highlights the potential of immune renormalization as a promising strategy in disease treatment.In recent years,our primary focus has centered onγδT cell-based immunotherapy,particularly pioneering the use of allogeneic Vδ2+γδT cells for treating late-stage solid tumors and tuberculosis patients.However,we recognize untapped potential and optimization opportunities to fully harnessγδT cell effector functions in immunotherapy.This review aims to thoroughly examineγδT cell immunology and its role in diseases.Initially,we elucidate functional differences betweenγδT cells and theirαβT cell counterparts.We also provide an overview of major milestones inγδT cell research since their discovery in 1984.Furthermore,we delve into the intricate biological processes governing their origin,development,fate decisions,and T cell receptor(TCR)rearrangement within the thymus.By examining the mechanisms underlying the anti-tumor functions of distinctγδT cell subtypes based onγδTCR structure or cytokine release,we emphasize the importance of accurate subtyping in understandingγδT cell function.We also explore the microenvironment-dependent functions ofγδT cell subsets,particularly in infectious diseases,autoimmune conditions,hematological malignancies,and solid tumors.Finally,we propose future strategies for utilizing allogeneicγδT cells in tumor immunotherapy.Through this comprehensive review,we aim to provide readers with a holistic understanding of the molecular fundamentals and translational research frontiers ofγδT cells,ultimately contributing to further advancements in harnessing the therapeutic potential ofγδT cells.

reatment of allergic inflammation and hyperresponsiveness by a simple compound, Bavachinin, isolated from Chinese herbs

气喘的发炎被一种类型调停 2 助手 T 房间(Th2 ) cytokine 反应，和堵住的 Th2 cytokine 生产被证明有一个有势力治疗学对气喘的发炎的效果。用 IL-4-green 荧光灯蛋白质(GFP ) 记者老鼠，我们表明了那 Bavachinin，从中国植物孤立的单个混合物，显著地禁止的 Th2 cytokine 生产包括 IL-4， IL-5 和 IL-13。尤其是，在 ovalbumin (卵) 的这复合几乎完全堵住的发炎敏化动物气喘模型。而且，我们证明这化学药品有选择地影响 GATA-3 的水平，由影响 GATA-3 mRNA 的稳定性最可能。第一次，我们的结果证明这单个混合物的潜在的治疗学的价值源于中国植物。

Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.

Vitamin C promotes the proliferation and effector functions of human γδ T cells

γδT cells are of interest as effector cells for cellular immunotherapy due to their HLA-non-restricted lysis of many different tumor cell types.Potential applications include the adoptive transfer of in vitro-expandedγδT cells.Therefore,it is important to optimize the culture conditions to enable maximal proliferative and functional activity.Vitamin C(L-ascorbic acid)is an essential vitamin with multiple effects on immune cells.It is a cofactor for several enzymes,has antioxidant activity,and is an epigenetic modifier.Here,we investigated the effects of vitamin C(VC)and its more stable derivative,L-ascorbic acid 2-phosphate(pVC),on the proliferation and effector function of humanγδT cells stimulated with zoledronate(ZOL)or synthetic phosphoantigens(pAgs).VC and pVC did not increaseγδT-cell expansion within ZOL-or pAg-stimulated PBMCs,but increased the proliferation of purifiedγδT cells and 14-day-expandedγδT-cell lines in response toγδT-cell-specific pAgs.VC reduced the apoptosis ofγδT cells during primary stimulation.While pVC did not prevent activation-induced death of pAg-restimulatedγδT cells,it enhanced the cell cycle progression and cellular expansion.Furthermore,VC and pVC enhanced cytokine production during primary activation,as well as upon pAg restimulation of 14-day-expandedγδT cells.VC and pVC also increased the oxidative respiration and glycolysis ofγδT cells,but stimulus-dependent differences were observed.The modulatory activity of VC and pVC might help to increase the efficacy ofγδT-cell expansion for adoptive immunotherapy.

Glucose metabolism controls humanγδ-cell-mediated tumor immunosurveillance in diabetes

Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induced Warburg effect type of bioenergetic profle in Vy9vδ2 T cells,leading to excessive lactate accumulation,which further inhibited lytic granule secretion by impairing the traffcking of cytolytic machinery to the Vy9vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro,in vivo and in patients.Strikingly,activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vy9vδ2 T cells.These results suggest that the impaired antitumor activity of Vy9vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.

Irreversible electroporation plus allogenic Vγ9Vδ2 T cells enhances antitumor effect for locally advanced pancreatic cancer patients

Immunotherapy has limited efficacy against locally advanced pancreatic cancer(LAPC)due to the presence of an immunosuppressive microenvironment(ISM).Irreversible electroporation(IRE)can not only induce immunogenic cell death,but also alleviate immunosuppression.This study aimed to investigate the antitumor efficacy of IRE plus allogeneicγδT cells in LAPC patients.A total of 62 patients who met the eligibility criteria were enrolled in this trial,then randomized into two groups(A:n=30 and B:n=32).All patients received IRE therapy and after receiving IRE,the group A patients received at least two cycles ofγδT-cell infusion as one course continuously.Group A patients had better survival than group B patients(median OS:14.5 months vs.11 months;median PFS:11 months vs.8.5 months).Moreover,the group A patients treated with multiple courses ofγδT-cell infusion had longer OS(17 months)than those who received a single course(13.5 months).IRE combined with allogeneicγδT-cell infusion is a promising strategy to enhance the antitumor efficacy in LAPC patients,yielding extended survival benefits.

Normalization cancer immunotherapy: blocking Siglec-15!

In a recent paper published in Nature medicine,Wang,J.,et al.identified Siglec-15 as a new candidate responsible for adaptive immune resistance and a potential target for normalization cancer immunotherapy.1 Cancer cells can develop various mechanisms to evade tumor-specific and non-specific attacks in the TME of solid tumors.2 Thus,systemic activation of immune systems or even increasing tumor-specific T cells in the peripheral does not necessarily lead to tumor regression.In fact,almost all the known strategies adopted by cancer for immune escape are also used for maintaining systemic homeostasis.

Inhibition of MALT1 paracaspase activity improves lesion recovery following spinal cord injury

Spinal cord injury(SCI) is a devastating traumatic injury that causes persistent, severe motor and sensory dysfunction. Immune responses are involved in functional recovery after SCI. Mucosa-associated lymphoid tissue lymphoma translocation 1(MALT1) has been shown to regulate the survival and differentiation of immune cells and to play a critical role in many diseases, but its function in lesion recovery after SCI remains unclear. In this paper, we generated KI(knock in) mice with a point mutation(C472 G) in the active center of MALT1 and found that the KI mice exhibited improved functional recovery after SCI.Fewer macrophages were recruited to the injury site in KI mice and these macrophages differentiated into anti-inflammatory macrophages. Moreover, macrophages from KI mice exhibited reduced phosphorylation of p65, which in turn resulted in decreased SOCS3 expression and increased pSTAT6 levels.Similar results were obtained upon inhibition of MALT1 paracaspase with the small molecule inhibitor‘‘MI-2' or the more specific inhibitor ‘‘MLT-827'. In patients with SCI, peripheral blood mononuclear cells(PBMC) displayed increased MALT1 paracaspase. Human macrophages showed reduced proinflammatory and increased anti-inflammatory characteristics following the inhibition of MALT1 paracaspase. These findings suggest that inhibition of MALT1 paracaspase activity in the clinic may improve lesion recovery in subjects with SCI.

CFTR is a negative regulator ofγδT cell IFN-γproduction and antitumor immunity

CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer development.However,little is known about the effects of CFTR on the differentiation and function ofγδT cells.In this study,we observed that CFTR was functionally expressed on the cell surface ofγδT cells.Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γrelease by peripheralγδT cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo.Interestingly,the molecular mechanisms underlying the regulation ofγδT cell IFN-γproduction by CFTR were either TCR dependent or related to Ca^(2+)influx.CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling.In addition,CFTR was found to modulate TCR-induced Ca^(2+)influx and membrane potential(Vm)-induced Ca^(2+)influx and subsequently regulate the calcineurin-NFATc1 signaling pathway inγδT cells.Thus,CFTR serves as a negative regulator of IFN-γproduction inγδT cells and the function of these cells in antitumor immunity.Our investigation suggests that modification of the CFTR activity ofγδT cells may be a potential immunotherapeutic strategy for cancer.

DPSN:扩增子测序引物标准化命名数据库(英文)

扩增子测序是目前用来衡量微生物多样性时使用最广泛的测序手段。因为其扩增的需要,所以选择合适的特定引物是必需的,且其对结果影响甚大。probeBase是目前最常用的记录了人工校正后的rRNA探针和引物的数据库。然而,我们发现probeBase中63.58%的引物存在不同程度的注释错误,包括命名重复、命名无规律以及匹配位置错误等。更严重的是,目前主流的短命名方式不具有唯一性,导致对应关系模糊不清。因此,我们定义了更简单可行的短命名标准并开发了新的引物科学命名数据库(DPSN),并对probeBase里的所有173个引物进行了校正,并新加入了4个新的改良引物以及38个针对大亚基的新引物。新的短命名规则包含3个基本要素:在正链5′端的位置、版本号和方向。此外在前面加入了识别大/小亚基以及主要针对的菌界的标志。使用DPSN,可以快速查找感兴趣区域对应的引物并比较不同版本的差异选择合适的引物。同时还能建立命名与序列的明确一一对应关系,避免歧义。

Gut microbiota have blood types as human

ABO blood group system was firstly recognized by Landsteiner in 1900[1].Since then,the antigens of the ABO system (A,B and H determinants,respectively)have been shown to encompass complex carbohydrate structures [2].A and B antigen were synthesized by the sequential action of glycosyltransferases,with A and B glycosyltransferases catalyzing the addition of N-acetylgalactosamine and D-galactose to precursor H antigen,respectively. Group O individuals lack such transferase enzymes and consequently continue to express the basic H structure only [3,4].It is determined that approximate 2million ABH glycan antigen sites are presented on each red blood cell [5].Additionally,the ABH antigens are widely expressed in other human ceils and tissues,including the sensory neurons,epithelium,the vascular endothelium and platelets [6].

Current progress in cd T-cell biology

T lymphocytes bearing c-and d-chain T-cell receptor heterodimers are named cd T cells.Interestingly,cd and ab T cells share the same progenitors,and they undergo a fate decision in the thymus.Functional differentiation of cd T cells occurs both inside and outside the thymus.Antigen recognition of cd T-cell receptors is very unique,and the responses frequently exhibit innate characteristics.Nevertheless,peripheral cd T cells exert a number of effector and regulatory functions.cd T cells rapidly produce cytokines like interferon(IFN)-c and IL-17 and promote inflammation,partly due to the inherent epigenetic and transcriptional programs,which facilitates a quick and extensive response.Moreover,cd T cells lyse target cells directly,and this is necessary for pathogen or tumor clearance.cd T cells can even serve as regulatory cells,and may contribute to immune suppression.Orchestration of cd T-cell and other immune cell interactions may be critical for host defense and immune regulation.Recently,cd T cells have been used for immunotherapy for infectious diseases and malignancy.In this review,we summarize the abstracts presented at the recent cd T cell Conference held from 19 to 21 May 2010,in Kiel,Germany(please see the website for details:http://www.gammadeltaconference.uni-kiel.de/index.html).

Dendritic cell-derived IL-27 p28 regulates T cell program in pathogenicity and alleviates acute graft-versus-host disease

Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood.In this study,utilizing mice with IL-27 p28 deficiency in dendritic cells(DCs),we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses,corresponding to aggravated aGVHD in mice.In addition,using single-cell RNA sequencing,we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL1R2^(+)TIGIT^(+)pathogenic CD4+T cells in the thymus at a steady state.Mechanistically,IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses,leading to the inhibition of Treg cell differentiation and function.Finally,patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28.Thus,our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development.IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.

Metabolic Control ofγδT Cell Function

Metabolic change is associated with cell activities,such as signal transduction,cell differentiation,and cell cycle.In the pathogenesis of autoimmune diseases,abnormal activation of T cells is often accompanied by changes in their metabolism.Conversely,the changes of metabolites can also regulate the proliferation,differentiation,and function of T cells.As a bridge between innate and adaptive immune responses,γδT cells have unique biological characteristics and functions.However,the immunometabolic mechanism ofγδT cells has been a novel field for research in recent years.In this review,we summarize the influence of metabolic pathways and nutrients onγδT cell function,and metabolic features ofγδT cell subsets,which may provide new insights in interventions targetingγδT cells in disease control.