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Subpopulations of Regulatory T cells are associated with subclinical atherosclerotic plaques,levels of LDL,and cardiorespiratory fitness in the elderly

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Journal of Sport and Health Science 2024年第3期13卷 288-296,I0002页

作者： tim Böttrich Pascal Bauer Vincent Gröβer Magdalena Huber Hartmann Raifer torsten Frech Svenja Nolte theresa Dombrowski Franz Cemic Natascha Sommer Robert Ringseis Klaus Eder Karsten Krüger Christopher Weyh Department of Exercise Physiology and Sports therapy Institute of Sports ScienceJustus-Liebig-UniversityGiessen 35394Germany Department of Cardiology and Angiology Justus-Liebig-University GiessenGiessen 35392Germany Institute for Systems Immunology Center for Tumor und ImmunologyMarburg 35032Germany tH Mittelhessen Department of Computer ScienceUniversity of Applied Sciences GiessenGiessen 35390Germany Department of Internal Medicine Universities of Giessen and Marburg Lung Center(UGMLC)Member of the German Center for Lung Research(DZL)Giessen 35394Germany Excellence Cluster Cardio-Pulmonary Institute(CPI) Justus-Liebig UniversityGiessen 35394Germany Institute of Animal Nutrition and Nutrition Physiology Justus-Liebig-University GiessenGiessen 35390Germany

Background:Atherosclerosis forms the pathological basis for the development of cardiovascular disease.Since pathological processes initially develop without clinically relevant symptoms,the identification of early markers in the subclinical stage plays an important role for initiating early interventions.there is evidence that Regulatory T cells(tregs)are involved in the development of atherosclerosis.therefore,the present study aimed to identify and investigate associations with tregs and their subsets in a cohort of healthy elderly individuals with and without subclinical atherosclerotic plaques(SAP).In addition,various lifestyle and risk factors,such as cardiorespiratory fitness,were investigated as associated signatures.Methods:A cross-sectional study was performed in 79 participants(male:n=50;age=63.6±3.7 years;body mass index=24.9±3.1 kg/m2;mean±SD)who had no previous diagnosis of chronic disease and were not taking medication.Ultrasound of the carotids to identify SAP,cardiovascular function measurement for vascular assessment and a cardiorespiratory fitness test to determine peak oxygen uptake were performed.Additionally,tests were conducted to assess blood lipids and determine glucose levels.Immunophenotyping of tregs and their subtypes(resting(rtregs)and effector/memory(mtregs))was performed by 8-chanel flow cytometry.Participants were categorized according to atherosclerotic plaque status.Linear and logistic regression models were used to analyze associations between parameters.Results:SAP was detected in a total of 29 participants.the participants with plaque were older(64.8±3.6 years vs.62.9±3.5 years)and had higher peripheral systolic blood pressure(133.8±14.7 mmHg vs.125.8±10.9 mmHg).the participants with SAP were characterized by a lower percentage of rtregs(28.8%±10.7%vs.34.6%±10.7%)and a higher percentage of mtregs(40.3%±14.7%vs.30.0%±11.9%).Multiple logistic regression identified age(odds ratio(OR)=1.20(95%confidence interval(95%CI):1.011.42))and mtregs(OR=1.05(95%CI:1.021.10))as independent

关键词： Cardiorespiratory fitness Elderly Regulatory T cells Subclinical atherosclerosis

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A pH-responsive polymersome depleting Regulatory T cells and blocking A2A receptor for cancer immunotherapy

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Nano Research 2022年第3期15卷 2324-2334页

作者： Binfen Shao Xuehui Huang Funeng Xu Jingmei Pan Yi Wang Shaobing Zhou School of Life Science and Engineering Southwest Jiaotong UniversityChengdu 610031China Key Laboratory of Advanced technologies of Materials Ministry of Education School of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu 610031China

the immunosuppressive tumor microenvironment(ItM)and low immunogenicity of tumors greatly limit cancer immunotherapy efficacy.the approach of solely depleting Regulatory T cells(tregs)cannot ameliorate ItM,but possibly worsen it since the produced apoptotic tregs will activate the A2A signaling pathway and cause more severe immune suppression.to address it,in this work a pH-responsive polymersome(CY/ZM@CS-BPA)based on chondroitin sulfate(CS)-poly(β-amino ester)is rationally developed.In the acidic tumor microenvironment,the tertiary amine groups in the polymersome will reverse from hydrophobic to hydrophilic due to protonation,which leads to the disintegration of nanostructures and the release of cyclophosphamide(CY)and A2A receptor(A2AR)antagonist ZM241385(ZM).CY can selectively deplete tregs.Additionally,CY can induce immunogenic cell death(ICD)of tumor cells,which results in the proapoptotic translocation of calreticulin to the cell surface,further initiating the antitumor immune responses.ZM can inhibit the activation of the adenosine A2A pathway,subsequently preventing the differentiation of CD4^(+)t cells into tregs and enhancing the cytotoxicity of CD8+t cells.As a result,the combination of depleting Regulatory T cells and blocking the A2A receptor can enhance cancer immunotherapy efficacy.

关键词： polymersome Regulatory T cells adenosine A2A pathway immunogenic cell death immunotherapy

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CD200Rhigghh neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing Regulatory T cells

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Cellular & Molecular Immunology 2024年第4期21卷 349-361页

作者： Ye Seon Kim Yu Sun Jeong Geon Ho Bae Ji Hyeon Kang Mingyu Lee Brian A.Zabel Yoe-Sik Bae Department of Biological Sciences Sungkyunkwan UniversitySuwon16419Republic of Korea Department of Health Science and technology SAIHSTSungkyunkwan UniversitySeoul06351Republic of Korea Palo Alto Veterans Institute for Research Veterans Affairs HospitalPalo AltoCA94304USA

Distinct neutrophil populations arise during certain pathological conditions.the generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear.In this study,using an experimental sepsis model that features immunosuppression,we identified a novel population of pathogenic CD200R^(high) neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory t(t_(reg))cells.Compared to their CD200R^(low)counterparts,sepsis-generated CD200Rhigh neutrophils exhibit impaired autophagy and dysfunction,with reduced chemotactic migration,superoxide anion production,and tNF-αproduction.Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis,and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200R^(high) neutrophils.the administration of anα-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge,leading to increased survival.transcriptome analysis revealed that CD200R^(high) neutrophils expressed high levels of Igf1,which elicits the generation of treg cells,while the administration of anα-CD200R antibody inhibited treg cell generation in a secondary infection model.taken together,our findings revealed a novel CD200R^(high) neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating treg cells.

关键词： Sepsis Neutrophils CD200R Autophagy IGF-1 Regulatory T cells

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Short-chain fatty acids ameliorate spinal cord injury recovery by regulating the balance of Regulatory T cells and effector IL-17^(+) γδ t cells

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第4期24卷 312-325页

作者： Pan LIU Mingfu LIU Deshuang XI Yiguang BAI Ruixin MA Yaomin MO Gaofeng ZENG Shaohui ZONG Department of Spine Osteopathic the First Affiliated Hospital of Guangxi Medical UniversityNanning 530021China Department of Orthopaedics the Third Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453000China Department of Orthopaedics Nanchong Central Hosipitalthe Second Clinical Institute of North Sichuan Medical CollegeNanchong 637000China Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry Guangxi Medical UniversityNanning 530021China College of Public Hygiene of Guangxi Medical University Nanning 530021China

Spinal cord injury(SCI)causes motor,sensory,and autonomic dysfunctions.the gut microbiome has an important role in SCI,while short-chain fatty acids(SCFAs)are one of the main bioactive mediators of microbiota.In the present study,we explored the effects of oral administration of exogenous SCFAs on the recovery of locomotor function and tissue repair in SCI.Allen’s method was utilized to establish an SCI model in Sprague-Dawley(SD)rats.the animals received water containing a mixture of 150 mmol/L SCFAs after SCI.After 21 d of treatment,the Basso,Beattie,and Bresnahan(BBB)score increased,the regularity index improved,and the base of support(BOS)value declined.Spinal cord tissue inflammatory infiltration was alleviated,the spinal cord necrosis cavity was reduced,and the numbers of motor neurons and Nissl bodies were elevated.Enzyme-linked immunosorbent assay(ELISA),real-time quantitative polymerase chain reaction(qPCR),and immunohistochemistry assay revealed that the expression of interleukin(IL)-10 increased and that of IL-17 decreased in the spinal cord.SCFAs promoted gut homeostasis,induced intestinal t cells to shift toward an anti-inflammatory phenotype,and promoted regulatory t(treg)cells to secrete IL-10,affecting treg cells and IL-17^(+)γδt cells in the spinal cord.Furthermore,we observed that treg cells migrated from the gut to the spinal cord region after SCI.the above findings confirm that SCFAs can regulate treg cells in the gut and affect the balance of treg and IL-17^(+)γδt cells in the spinal cord,which inhibits the inflammatory response and promotes the motor function in SCI rats.Our findings suggest that there is a relationship among gut,spinal cord,and immune cells,and the“gut-spinal cord-immune”axis may be one of the mechanisms regulating neural repair after SCI.

关键词： Short-chain fatty acids(SCFAs) Spinal cord injury(SCI) Regulatory T cells IL-17^(+)γδt cells Neuroprotection Inflammation Motor function recovery

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CD4^(+)CD25^(+) Regulatory T cells decreased future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy

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World Journal of Gastrointestinal Surgery 2023年第5期15卷 917-930页

作者： Wei Wang Chun-Hui Ye Zhen-Feng Deng Ji-Long Wang Ling Zhang Li Bao Bang-Hao Xu Hai Zhu Ya Guo Zhang Wen Department of Hepatobiliary Surgery The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina Department of Radiology The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina Key Laboratory of Cancer Prevention and therapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin 300000China

BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)is an innovative surgical approach for the treatment of massive hepatocellular carcinoma(HCC),the key to successful planned stage 2 ALPPS is future liver remnant(FLR)volume growth,but the exact mechanism has not been elucidated.the correlation between Regulatory T cells(tregs)and postoperative FLR regeneration has not been reported.AIM to investigate the effect of CD4^(+)CD25^(+)tregs on FLR regeneration after ALPPS.MEtHODS Clinical data and specimens were collected from 37 patients who developed massive HCC treated with ALPPS.Flow cytometry was performed to detect changes in the proportion of CD4^(+)CD25^(+)tregs to CD4^(+)t cells in peripheral blood before and after ALPPS.to analyze the relationship between peripheral blood CD4^(+)CD25^(+)treg proportion and clinicopathological information and liver volume.RESULtS the postoperative CD4^(+)CD25^(+)treg proportion in stage 1 ALPPS was negatively correlated with the amount of proliferation volume,proliferation rate,and kinetic growth rate(KGR)of the FLR after stage 1 ALPPS.Patients with low treg proportion had significantly higher KGR than those with high treg proportion(P=0.006);patients with high treg proportion had more severe postoperative pathological liver fibrosis than those with low treg proportion(P=0.043).the area under the receiver operating characteristic curve between the percentage of tregs and proliferation volume,proliferation rate,and KGR were all greater than 0.70.CONCLUSION CD4^(+)CD25^(+)tregs in the peripheral blood of patients with massive HCC at stage 1 ALPPS were negatively correlated with indicators of FLR regeneration after stage 1 ALPPS and may influence the degree of fibrosis in patients’livers.treg percentage was highly accurate in predicting the FLR regeneration after stage 1 ALPPS.

关键词： Associating liver partition and portal vein ligation for staged hepatectomy Regulatory T cells Future liver remnant

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Regulatory T cells: A New target of Chinese Medicine in treatment of Atherosclerosis

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Chinese Journal of Integrative Medicine 2021年第11期27卷 867-873页

作者： LIANG Zhao-ying QIAN Cai-wen LAN tao-hua ZENG Qiao-huang LU Wei-hui JIANG Wei State Key Laboratory of Dampness Syndrome of Chinese Medicine Department of Cardiologythe Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou510020China Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and treatment of Refractory Chronic Diseases Guangzhou510020China the Second Clinical Medical College of Guangzhou University of Chinese Medicine Guangzhou510405China the Second Affiliated Hospital of Guangzhou University of Chinese Medicine Guangzhou510020China

Inflammation and immune disorders are integral to the occurrence and progression of atherosclerosis(AS).With the role of Regulatory T cells(tregs)in immune regulation attracting attention,it has been widely accepted that treg decrease and dysfunction are involved in AS pathogenesis.Chinese medicine(CM)has the advantages of being dual-directional,multi-targeted,and having minimal side effects in immune regulation.the anti-atherosclerosis effects of CM via treg modulation have been revealed in clinical and animal studies.therefore,this article reviews existing research on tregs,the relationship between tregs and AS,and the progress of CM for treating and prevention of atherosclerotic cardio-cerebrovascular diseases by regulating tregs.Although the underlying mechanisms remain to be elucidated,CM treatment targeting treg cells might provide a promising and novel future approach for prevention and treatment of AS.

关键词： Chinese medicine atherosclerosis Regulatory T cells immunization inflammation

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Differences in phenotype,homing properties and suppressive activities of Regulatory T cells induced by epicutaneous,oral or sublingual immunotherapy in mice sensitized to peanut

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Cellular & Molecular Immunology 2017年第9期14卷 770-782页

作者： Vincent Dioszeghy Lucie Mondoulet Emilie Puteaux Véronique Dhelft Mélanie Ligouis Camille Plaquet Christophe Dupont Pierre-Henri Benhamou Research Department DBV TechnologiesParis92220France Pédiatrie-Gastroentérologie Université Paris Descartes&APHP-Hôpital NeckerParis75743France

Allergen-specific immunotherapy has been proposed as an attractive strategy to actively treat food allergy using the following three different immunotherapy routes:oral(OIt),sublingual(SLIt)and epicutaneous(EPIt)immunotherapy.Regulatory T cells(tregs)have been shown to have a pivotal role in the mechanisms of immunotherapy.the aim of this study was to compare the phenotype and function of tregs induced in peanut-sensitized BALB/c mice using these three routes of treatment.We show that although EPIt,OIt and SLIt were all able to effectively desensitize peanut-sensitized mice,they induced different subsets of tregs.Foxp3+tregs were induced by the three treatment routes but with greater numbers induced by EPIt.EPIt and OIt also increased the level of LAP+tregs,whereas SLIt induced IL-10+cells.the suppressive activity of EPIt-induced tregs did not depend on IL-10 but required CtLA-4,whereas OIt acted through both mechanisms and SLIt was strictly dependent on IL-10.Moreover,the three routes influenced the homing properties of induced tregs differently,with a larger repertoire of chemokine receptors expressed by EPIt-induced tregs compared with OIt-and SLIt-induced cells,resulting in different protective consequences against allergen exposure.Furthermore,whereas OIt-or SLIt-induced tregs lost their suppressive activities after treatment was discontinued,the suppressive activities of EPIt-induced tregs were still effective 8 weeks after the end of treatment,suggesting the induction of a more long-lasting tolerance.In summary,EPIt,OIt and SLIt mediated desensitization through the induction of different subsets of tregs,leading to important differences in the subsequent protection against allergen exposure and the possible induction of tolerance.

关键词： allergy immunotherapy mechanisms Regulatory T cells

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Survival and maintenance of Regulatory T cells require the kinase tAK1

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Cellular & Molecular Immunology 2015年第5期12卷 572-579页

作者： Jae-Hoon Chang Hongbo Hu Shao-Cong Sun Department of Immunology The University of Texas MD Anderson Cancer Center 7455 Fannin Street Box 902 Houston TX 77030 USA Center for Inflammation and Cancer The University of Texas MD Anderson Cancer Center 7455 Fannin Street Box 902 Houston TX 77030 USA the University of texas Graduate School of Biomedical Sciences at Houston Houston TX 77030 USA College of Pharmacy Yeungnam University Gyeongsan 712- 749 Republic of Korea

regulatory t （treg） cells play a central role in regulating peripheral immune tolerance and preventing autoimmunity. Despite the extensive studies on the development of treg cells, the molecular mechanisms that maintain the population of committed treg cells remain poorly understood. We show here that treg-conditional ablation of the kinase tAK1 reduced the number of treg cells in the peripheral lymphoid organs, causing abnormal activation of conventional t cells and autoimmune symptoms. Using an inducible gene knockout approach, we further demonstrate that tAK1 is crucial for the survival of treg cells. Expression of a constitutively active IKB kinase partially restored the level of treg cells in the tAKItreg-KO mice. these results suggest a crucial role for tAK1 for maintaining the survival of committed treg cells under physiololzical conditions.

关键词： Regulatory T cells autoimmunity tAK1 IKK Foxp3

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Human mesenchymal stromal cells enhance the immunomodulatory function of CD8＋CD28- Regulatory T cells

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Cellular & Molecular Immunology 2015年第6期12卷 708-718页

作者： Qiuli Liu Haiqing Zheng Xiaoyong Chen Yanwen Peng Weijun Huang Xiaobo Li Gang Li Wenjie Xia Qiquan Sun an Andy Peng Xiang Cell-gene therapy translational Medicine Research Center The Third Affiliated Hospital Zhongshan School of Medicine Sun Yat-sen University Guangzhou Guangdong China Center for Stem Cell Biology and tissue Engineering The Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education Sun Yat-sen University Guangzhou China Department of Rehabilitation Medicine The Third Affiliated Hospital Sun Yat-sen University Guangzhou China Institute of Blood transfusion Guangzhou Blood Centre Guangzhou China Department of Renal transplantation The Third Affiliated Hospital Sun Yat- sen University Guangzhou China Department of Biochemistry Zhongshan Medical School Sun Yat-sen University Guangzhou China these authors contributed enuallv tn this wnrk

One important aspect of mesenchymal stromal cells （MSCs）-mediated immunomodulation is the recruitment and induction of regulatory t （treg） cells. However, we do not yet know whether MSCs have similar effects on the other subsets of treg cells. Herein, we studied the effects of MSCs on CD8＋CD28- treg cells and found that the MSCs could not only increase the proportion of CD8＋CD28- t cells, but also enhance CD8＋CD28-t cells＇ ability of hampering naive CD4＋ t-cell proliferation and activation, decreasing the production of IFN-γ by activated CD4＋ t cells and inducing the apoptosis of activated CD4＋ t cells. Mechanistically, the MSCs affected the functions of the CD8＋CD28- t cells partially through moderate upregulating the expression of IL-10 and FasL. the MSCs had no distinct effect on the shift from CD8＋CD28＋ t cells to CD8＋CD28- t cells, but did increase the proportion of CD8＋CD28- t cells by reducing their rate of apoptosis. In summary, this study shows that MSCs can enhance the regulatory function of CD8＋CD28- treg cells, shedding new light on MSCs-mediated immune regulation.

关键词： antigens CD28 CD8-positive t cells mesenchymal stromal cells Regulatory T cells

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tissue resident Regulatory T cells： novel therapeutic targets for human disease

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Cellular & Molecular Immunology 2015年第5期12卷 543-552页

作者： Xiaohui Zhou Jiayou tang Hao Cao Huimin Fan Bin Li Research Center for translational Medicine Shanghai East Hospital Tongji University School of Medicine Shanghai Heart Failure Research Center Department of Heart Failure Shanghai East Hospital Tongji University School of Medicine Key Laboratory of Molecular Virology & Immunology Unit of Molecular Immunology Institute Pasteur of Shanghai Shanghai Institutes for Biological Sciences Shanghai 200120 China

Over the past decade, the ability of Regulatory T cells （tregs） to suppress multiple types of immune cells has received tremendous attention. Mounting evidence has revealed that tissue resident tregs control non-immunological processes of their target tissues and contribute to a plethora of human diseases. the identification of novel tissue-specific tregs has highlighted their heterogeneity and complexity. this review summarizes the recent findings for visceral adipose tissue CD4＋Foxp3＋ Regulatory T cells （VAt tregs）, muscle tregs, bone tregs and skin memory tregs, with a focus on their unique functions in local tissues. this interpretation of the roles of tissue-specific tregs and of their involvement in disease progression provides new insight into the discovery of potential therapeutic targets of human diseases.

关键词： Regulatory T cells tissue tregs VAt tregs Muscle Repair Areg tumor Bone Skin memory tregs

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