Distribution of Microbiota in Fine Particulate Matter Particles in Guangzhou, China

Objective High PM2.5 concentration is the main feature of increasing haze in developing states,but information on its microbial composition remains very limited.This study aimed to determine the composition of microbiota in PM2.5 in Guangzhou,a city located in the tropics in China.Methods In Guangzhou,from March 5th to 10th,2016,PM2.5 was collected in middle volume air samplers for 23 h daily.The 16 S rDNA V4 region of the PM2.5 sample extracted DNA was investigated using high-throughput sequence.Results Among the Guangzhou samples,Proteobacteria,Bacteroidetes,Firmicutes,Cyanobacteria,and Actinobacteria were the dominant microbiota accounting for more than 90%of the total microbiota,and Stenotrophomonas was the dominant gram-negative bacteria,accounting for 21.30%–23.57%.We examined the difference in bacterial distribution of PM2.5 between Beijing and Guangzhou at the genus level;Stenotrophomonas was found in both studies,but Escherichia was only detected in Guangzhou.Conclusion In conclusion,the diversity and specificity of microbial components in Guangzhou PM2.5 were studied,which may provide a basis for future pathogenicity research in the tropics.

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.

The molecular mechanisms supporting the homeostasis and activation of dendritic epidermal T cell and its role in promoting wound healing

The epidermis is the outermost layer of skin and the first barrier against invasion.Dendritic epidermal T cells(DETCs)are a subset ofT cells and an important component of the epidermal immune microenvironment.DETCs are involved in skin wound healing,malignancy and autoim-mune diseases.DETCs secrete insulin-like growth factor-1 and keratinocyte growth factor for skin homeostasis and re-epithelization and release inflammatory factors to adjust the inflammatory microenvironment of wound healing.Therefore,an understanding of their development,activation and correlative signalling pathways is indispensable for the regulation of DETCs to accelerate wound healing.Our review focuses on the above-mentioned molecular mechanisms to provide a general research framework to regulate and control the function of DETCs.

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.

Spectrum of Cytogenomic Abnormalities Revealed by Array Comparative Genomic Hybridization on Products of Conception Culture Failure and Normal Karyotype Samples

Approximately 30% of pregnancies after implantation end up in spontaneous abortions, and 50% of them are caused by chromosomal abnormalities. However, the spectrum of genomic copy number variants （CNVs） in products of conception （POC） and the underlying gene- dosage-sensitive mechanisms causing spontaneous abortions remain largely unknown. In this study, array comparative genornic hybridiza- tion （aCGH） analysis was performed as a salvage procedure for 128 POC culture failure （POC-CF） samples and as a supplemental procedure for 106 POC normal karyotype （POC-NK） samples. Chromosomal abnormalities were detected in 10% of POC-CF and pathogenic CNVs were detected in 3.9% of POC-CF and 5.7% of POC-NK samples. Compiled results from this study and relevant case series through a literature review demonstrated an abnormality detection rate （ADR） of 35% for chromosomal abnormalities in POC-CF samples, 3.7% for pathogenic CNVs in POC-CF samples, and 4.6% for pathogenic CNVs in POC-NK samples. Ingenuity Pathway Analysis （IPA） was performed on the genes from pathogenic CNVs found in POC samples. The denoted primary gene networks suggested that apoptosis and cell proliferation pathways are involved in miscarriage. In summary, a similar spectrum of cytogenomic abnormalities was observed in POC culture success and POC-CF samples. A threshold effect correlating the number of dosage-sensitive genes in a chromosome with the observed frequency of autosomai trisomy is proposed. A rationalized approach using firstly fluorescence in situ hybridization （FISH） testing with probes of chromosomes X/Y/ 18, 13/21, and 15/16/22 for common aneuploidies and polyploidies and secondly aCGH for other cytogenomic abnormalities is recommended for POC-CF samples.

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.

单细胞转录组和单细胞染色质开放性图谱解析小鼠γδT细胞异质性

γδT细胞具有重要的免疫监视功能,其不同亚群在维持组织稳态和局部免疫反应中发挥不同作用,但是γδT细胞的异质性尚未完全解析.本文对小鼠胸腺、脾脏和淋巴结中的γδT细胞开展了单细胞转录和染色质开放性组学分析,系统地解析了其异质性.经典的γδT1(IFN-γ^(+))和γδT17(IL-17A;)亚群内部也存在显著的异质性,作者推断了其潜在调控机制.通过对胸腺γδT细胞进行拟时序分析,作者构建了其发育轨迹.有意思的是,作者发现胸腺中存在一群独立于γδT1和γδT17的新亚群—GZMA;γδT细胞,并且发现该亚群具有前体细胞特征.作者还通过转录子活性分析、转录因子识别基序富集发现了一个新的γδT17转录抑制因子—NR1D1,并利用基因敲除小鼠进行了验证.综上,本文构建了小鼠γδT单细胞转录图谱和单细胞染色质开放性图谱,为深入解析γδT细胞异质性和亚群调控机制提供了宝贵的资源库.

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.

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.