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 mar...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 risk factors for SAP.Stepwise linear regression could reveal an association of peak oxygen uptake(b=0.441),low-density lipoprotein(LDL)(b=0.096),and SAP(b=6.733)with mTregs and LDL(b=0.104)with rTregs.Conclusion:While at an early stage of SAP,the total proportion of Tregs gives no indication of vascular changes,this is indicated by a shift in the Treg subgroups.Factors such as serum LDL or cardiopulmonary fitness may be associated with this shift and may also be additional diagnostic indicators.This could be used to initiate lifestyle-based preventive measures at an early stage,which may have a protective effect against disease progression.展开更多
Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects ...Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects and possible underlying mechanisms of MFGM on cow’s milk allergy(CMA)in aβ-lactoglobulin(BLG)-induced allergic mice model.MFGM was supplemented to allergic mice induced by BLG at a dose of 400 mg/kg body weight.Results demonstrated that MFGM alleviated food allergy symptoms,decreased serum levels of lipopolysaccharide,pro-inflammatory cytokines,immunoglobulin(Ig)E,Ig G1,and Th2 cytokines including interleukin(IL)-4,while increased serum levels of Th1 cytokines including interferon-γand regulatory T cells(Tregs)cytokines including IL-10 and transforming growth factor-β.MFGM modulated gut microbiota and enhanced intestinal barrier of BLG-allergic mice,as evidenced by decreased relative abundance of Desulfobacterota,Rikenellaceae,Lachnospiraceae,and Desulfovibrionaceae,while increased relative abundance of Bacteroidetes,Lactobacillaceae and Muribaculaceae,and enhanced expressions of tight junction proteins including Occludin,Claudin-1 and zonula occludens-1.Furthermore,MFGM increased fecal short-chain fatty acids(SCFAs)levels,which elevated G protein-coupled receptor(GPR)43 and GPR109A expressions.The increased expressions of GPR43 and GPR109A induced CD103+dendritic cells accumulation and promoted Tregs differentiation in mesenteric lymph node to a certain extent.In summary,MFGM alleviated CMA in a BLG-induced allergic mice model through enhancing intestinal barrier and promoting Tregs differentiation,which may be correlated with SCFAs-mediated activation of GPRs.These findings suggest that MFGM may be useful as a promising functional ingredient against CMA.展开更多
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 ...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.展开更多
BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechan...BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechanism of PTH in an AIH mouse model by determining the changes in gut microbiota structure and memory regulatory T(mTreg)cells functional levels.METHODS Following induction of the AIH mouse model induced by Concanavalin A(Con A),prophylactic administration of PTH was given for 10 d.The levels of mTreg cells were measured by flow cytometry,and intestinal microbiota was analyzed by 16S rRNA analysis,while western blotting was used to identify activation of the toll-like receptor(TLR)2,TLR4/nuclear factor-κB(NF-κB),and CXCL16/CXCR6 signaling pathways.RESULTS In the liver of mice with AIH,PTH relieved the pathological damage and reduced the numbers of T helper type 17 cells and interferon-γ,tumor necrosis factor-alpha,interleukin(IL)-1β,IL-2,IL-6,and IL-21 expression.Simultaneously,PTH stimulated the abundance of helpful bacteria,promoted activation of the TLR2 signal,which may enhance Treg/mTreg cells quantity to produce IL-10,and suppressed activation of the TLR4/NF-κB and CXCL16/CXCR6 signaling pathways.CONCLUSION PTH regulates intestinal microbiota balance and restores mTreg cells to alleviate experimental AIH,which is closely related to the TLR/CXCL16/CXCR6/NF-κB signaling pathway.展开更多
BACKGROUND: Although regulatory T cells(Tregs) are key to the maintenance of immunologic homeostasis and tolerance, little is known about Treg-mediated immunosuppression in the stage of sepsis. This article aimed to r...BACKGROUND: Although regulatory T cells(Tregs) are key to the maintenance of immunologic homeostasis and tolerance, little is known about Treg-mediated immunosuppression in the stage of sepsis. This article aimed to review the current literature on the role of Tregs in the pathophysiology of septic response, attempting to investigate the role of Tregs in immune dysfunction during sepsis.DATA SOURCES: A literature search was conducted in January 2014 using the China National Knowledge Infrastructure and Pub Med. Articles on the role of Tregs in immune dysfunction during sepsis were identified.RESULTS: The identified articles indicated that Treg levels can be used for the assessment of the course of sepsis. The inhibition of Treg activity can promote the recovery of immune function.CONCLUSION: Since the mechanism of Tregs is complex during the sepsis, more studies are needed.展开更多
Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma(HCC).Factors,including carcinogens,infection of hepatitis viruses,alcohol abuse,and non-alcoholic fa...Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma(HCC).Factors,including carcinogens,infection of hepatitis viruses,alcohol abuse,and non-alcoholic fatty liver disease(NAFLD),can induce HCC initiation and promote HCC progression.The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide.However,the benefit of current therapeutic options is still limited.Intrahepatic immunity plays critically important roles in HCC initiation,development,and progression.Regulatory T cells(Tregs)and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC.Therefore,targeting Tregs and blocking their mediated factors may prevent HCC progression.This review summarizes the functions of Tregs in HCC-inducing factors including alcoholic and NAFLD,liver fibrosis,cirrhosis,and viral infections.Overall,a better understanding of the role of Tregs in the development and progression of HCC provides treatment strategies for liver cancer treatment.展开更多
OBJECTIVE Experimental autoimmune encephalomyelitis(EAE),the classical animal model for multiple sclerosis(MS)is triggered by an impaired balance of T helper(Th)cells and regulatory T(Tregs)cells.Matrine(MAT),a quinol...OBJECTIVE Experimental autoimmune encephalomyelitis(EAE),the classical animal model for multiple sclerosis(MS)is triggered by an impaired balance of T helper(Th)cells and regulatory T(Tregs)cells.Matrine(MAT),a quinolizidine alkaloid derived from the herb Radix Sophorae Flave,has been shown to ameliorate the clinical signs,inflammatory infiltration,demyelination in acute EAE rats.However,whether MAT protect from EAE by adjusting Th and Treg cells response in specific-cellular and molecular level is unknown.METHODS Herein,MAT was tested for its effects on Th1,Th2,Th17 and Treg cells in the spinal cord of EAE mice and splenocyte-extracted from EAE mice with MOG35-55-restimulated,respectively.RESULTS Our findings revealed that MAT significantly inhibit the proliferation of splenocyte,and remarkably down-regulate the differentiation of Th1/Th17 cells with decreased expressions of CD4+IFN-γ+cells and CD4+IL-17+cells in vivo and IL-17,IFN-γ,ROR-γt,T-bet in vitro,meanwhile it dramatically up-regulate the Th2/Treg cells response associated with increased levels of CD4+TGF-β+1cells and CD4+IL-10+cells in vivo and IL-4,IL-10,TGF-β1,Foxp3 and GATA3in vitro.CONCLUSION Considering the effective therapeutic effects of MAT on EAE,it′s worth to find its new values on other autoimmune diseases.展开更多
Objective:To explore immunotherapy effectiveness of the CD4^(+)CD25^(+) regulatory T cells for treating female mouse with recurrent spontaneous abortion(RSA)by animal experiments.Methods:Mononuclear lymphocytes were i...Objective:To explore immunotherapy effectiveness of the CD4^(+)CD25^(+) regulatory T cells for treating female mouse with recurrent spontaneous abortion(RSA)by animal experiments.Methods:Mononuclear lymphocytes were isolated from the blood(instead of cord blood)of new-born baby of KunMing Bai mouse or BALB/c male mouse with normal birth ability(as unrelated third party blood source)by density gradient centrifuga-tion method.The CD4^(+)CD25^(+) regulatory T cells were selected by magnetic-activated cell sorting from mononuclear cells of cord blood cells.CBA/J female mouse copulated with DBA/2J male mouse was utilized as RSA animal model.Pregnant RSA mice were injected different types of lymphocytes through tail vein.Independent sample t-test was used to analyze the data from each group.Results:The proportion of CD4^(+)CD25^(+)T cells in CD4^(+)T cells was(17.49±0.60)%in CD4^(+)CD25^(+) regulatory T cells injection group,which was statistical significant higher than that of mononuclear lymphocyte injection group(14.68±0.83)%,sterile PBS group(9.54±0.85)%or no injection group(9.28±0.68)%(p<.05,t-value was 4.754,13.242 and 15.621,respec-tively).The Foxp3 relative protein expression level of CD4^(+)CD25^(+) regulatory T cells injected group was 5.85±0.45,which was also significant higher than that of mononuclear lymphocyte injection(2.86±0.54),sterile PBS group(1.08±0.16)or no injection group(1.00±0.00)(p<.05,t-value was 7.276,17.227 and 18.635,respectively).Finally,two times of CD4^(+)CD25^(+)T cell injected group at the 4 th and 8 th day had well effect for RSA mouse,and embryo sorption rate was(4.92±0.08)%,which significant lower than that of two times of mononuclear lymphocyte injected group(13.07±0.06)%,sterile PBS group(23.11±0.12)%,or no injection group(25.47±0.11)%(p<.05,t-value was-2.603,-4.012 and-4.700,respectively).Conclusions:Pregnant mouse with RSA injected CD4^(+)CD25^(+)T cells several times for immunotherapy can get better effec-tiveness than that of pregnant mouse injected traditional mononuclear cells.展开更多
Objective To study the changes of lymphocyte subsets and regulatory T cells in peripheral blood of patients with acute leukemia(AL) and its clinical significance.Methods The different levels of peripheral blood lympho...Objective To study the changes of lymphocyte subsets and regulatory T cells in peripheral blood of patients with acute leukemia(AL) and its clinical significance.Methods The different levels of peripheral blood lymphocyte subsets and regulatory T cells of 60 AL patients and 40 normal controls were detected with flow cytometry.Results Compared with the normal controls,the percentages of CD3+ T cells,CD4+ T cells,CD16+CD56+ NK cells and the ratio of CD4+ /CD8+ obviously decreased in newly diagnosed AL group(P <0.05),while their percentages of CD8+ T cells and CD19+ B cells significantly increased(P <0.01).The percentage of CD4+ T cells and the ratio of CD4+ /CD8+ in acute lymphoblastic leukemia(ALL) group were much lower than those in acute myelogenous leukemia(AML) group(P <0.01).Compared with these in control group,the proportions of CD4+ CD25high Treg cells and CD4+ CD25+ T cells in newly diagnosed AL group were significantly increased(P <0.01).Conclusion Cellular immune function is significantly abnormal in patients with AL.Compared with AML patients,ALL patients had poorer cellular immune function.The increased CD4 + CD25high Treg cells might be one of the important reasons of immunosuppression in AL.Detection of lymphocyte subsets and regulatory T cells is of clinical value on the evaluation of therapeutic effect and prognosis in AL patients.展开更多
AIM: To investigate the role of regulatory T(Treg) cells in CD4+ T cell-mediated bladder autoimmune inflammation.METHODS: Urothelium-ovalbumin(URO-OVA)/OTII mice, a double transgenic line that expresses the membrane f...AIM: To investigate the role of regulatory T(Treg) cells in CD4+ T cell-mediated bladder autoimmune inflammation.METHODS: Urothelium-ovalbumin(URO-OVA)/OTII mice, a double transgenic line that expresses the membrane form of the model antigen(Ag) OVA as a self-Ag on the urothelium and the OVA-specific CD4+ T cell receptor specific for the I-Ab/OVA323-339 epitope in the periphery, were developed to provide an autoimmune environment for investigation of the role of Treg cells in bladder autoimmune inflammation. To facilitate Treg cell analysis, we further developed URO-OVAGFP-Foxp3/OT-II mice, a derived line of URO-OVA/OT-II mice that express the green fluorescent protein(GFP)-forkhead box protein P3(Foxp3) fusion protein. RESULTS: URO-OVA/OT-II mice failed to develop bladder inflammation despite the presence of autoreactive CD4+ T cells. By monitoring GFP-positive cells, bladder infiltration of CD4+ Treg cells was observed in URO-OVAGFP-Foxp3/OTII mice. The infiltrating Treg cells were functionally active and expressed Treg cell effector molecule as well as marker m RNAs including transforming growth factor-b, interleukin(IL)-10, fibrinogen-like protein 2, and glucocorticoid-induced tumor necrosis factor receptor(GITR). Studies further revealed that Treg cells from URO-OVAGFP-Foxp3/OT-II mice were suppressive and inhibited autoreactive CD4+ T cell proliferationand interferon(IFN)-g production in response to OVA Ag stimulation. Depletion of GITR-positive cells led to spontaneous development of bladder inflammation and expression of inflammatory factor m RNAs for IFN-g, IL-6, tumor necrosis factor-a and nerve growth factor in URO-OVAGFP-Foxp3/OT-II mice. CONCLUSION: Treg cells specific for bladder epithelial Ag play an important role in immunological homeostasis and the control of CD4+ T cell-mediated bladder autoimmune inflammation.展开更多
Regulatory T cells(Treg cells) are a group of negative regulatory cells that include nonspecific immune regulation CD4+ T cells. Treg cells inhibit the function of other immune cells. CD_4^+ CD_(25)^+ FOXP_3^+ is a Tr...Regulatory T cells(Treg cells) are a group of negative regulatory cells that include nonspecific immune regulation CD4+ T cells. Treg cells inhibit the function of other immune cells. CD_4^+ CD_(25)^+ FOXP_3^+ is a Treg cell that is co-expressed by CD_(25) and FOXP_3. The expression of Treg cells is up-regulated in the focal microenvironment and peripheral blood of patients infected with human papilloma virus(HPV). Further studies on Treg cells indicate that their potential clinical applications in the treatment of HPV infection.展开更多
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 un...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 CD200^(Rhigh) 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 CD200Rhigh 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 CD200^(Rhigh) 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 CD200^(Rhigh) neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating Treg cells.展开更多
Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Per...Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.展开更多
Background: The absence of a safe and effective therapy for recurrent spontaneous abortion due to a maternofetal failure in immunological tolerance remains an intractable clinical obstacle for surgeons. Recently, trad...Background: The absence of a safe and effective therapy for recurrent spontaneous abortion due to a maternofetal failure in immunological tolerance remains an intractable clinical obstacle for surgeons. Recently, traditional Chinese medicine has become a feasible alternative for certain diseases, including recurrent spontaneous abortion. However, because of the complex composition of the traditional Chinese medicine formula, its action mechanism remains unclear. Methods: We selected two isolated active ingredients (RAMP and baicalin) from the traditional Chinese medicine formula and used an abortion-prone CBA/J × DBA/2 model to simulate human RSA and compared the changes in fetal resorption rate, Treg cell percentage, and relevant cytokines before and after combination therapy. In addition, The mechanisms were preliminarily discussed using in vitro differentiation models. Results: In CBA/J × DBA/2 abortion-prone mice, the combination therapy resulted in a lower embryo resorption rate compared to that obtained with individual delivery of either RAMP or baicalin, thereby playing an embryo-protective role through the increase in Treg cells for the maintenance of maternal-fetal immune tolerance. In in vitro primary cell differentiation experiments, the concentration of Treg cells significantly increased from 11% to 17.9% after the combination therapy compared to that of the single administration group. Conclusion: the synergistic effects of RAMP and baicalin were responsible for Treg differentiation. The present study provides a solid basis for improving the applicability of traditional Chinese herbs in the treatment of recurrent spontaneous abortion.展开更多
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 p...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.展开更多
Functional Tregs play a key role in tumor development and progression,representing a major barrier to anticancer immunity.The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvir...Functional Tregs play a key role in tumor development and progression,representing a major barrier to anticancer immunity.The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood.Herein,by using NMR,chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses,we demonstrate that the tumoral carbohydrate A10(Ca10),a cell-surface carbohydrate derived from Ehrlich’s tumor(ET)cells,is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs.Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming,PD-L1,IL-10,and IDO.Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features.In solid ET-bearing mice,we found positive correlations between Ca10 serum levels,tumor size and splenic Treg numbers.Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice.Remarkably,we provide evidence supporting the presence of a circulating human Ca10 counterpart(Ca10H)and show,for the first time,that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals.Of note,these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases.Collectively,we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer.The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.展开更多
Although DNA mutation drives stem cell aging,how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood.Here,using a mouse model of irradiation-induced premature aging and middl...Although DNA mutation drives stem cell aging,how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood.Here,using a mouse model of irradiation-induced premature aging and middle-aged mice,we show that DNA mutation accumulation in hematopoietic stem cells(HSCs)during aging upregulates their surface expression of major histocompatibility complex class II(MHCII).MHCII upregulation increases the chance for recognition by bone marrow(BM)-resident regulatory T cells(Tregs),resulting in their clonal expansion and accumulation in the HSC niche.On the basis of the establishment of connexin 43(Cx43)-mediated gap junctions,BM Tregs transfer cyclic adenosine monophosphate(cAMP)to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A(PKA)signaling.Importantly,targeting the HSC–Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs.These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.展开更多
Objective Thyroid-associated ophthalmopathy(TAO)is an autoimmune disorder involving the orbital tissue.This study aimed to understand the role of regulatory T cells(Tregs)in TAO during 12-week systemic glucocorticoid(...Objective Thyroid-associated ophthalmopathy(TAO)is an autoimmune disorder involving the orbital tissue.This study aimed to understand the role of regulatory T cells(Tregs)in TAO during 12-week systemic glucocorticoid(GC)treatment.Methods Thirty-two moderate-severe TAO patients with a clinical activity score(CAS)≥3/7 or with prolonged T2 relaxation time(T2RT)on at least one side of extraocular muscle(EOM)were enrolled.The percentage of the peripheral CD4+CD25(high)CD127(−/low)Tregs was analyzed using flow cytometry before and after the GC treatment.The activity and severity of TAO,T2RT,and the clinical outcomes after the GC treatment were assessed.Their correlation with the peripheral Tregs was investigated.Results There was no significant association between the baseline Treg fraction and the activity and severity of TAO or the treatment response.A significant reduction of Tregs was observed after the GC therapy merely in patients without any clinical improvement.Conclusion Treg reduction after systemic GC therapy is indicative of a poor therapeutic response.Accordingly,dynamic alterations of Tregs could help to evaluate the effectiveness of the GC treatment.展开更多
Methylprednisolone pulse treatment is currently used fo r optic neuritis.It can speed visual recovery,but does not improve the ultimate visual outcomes.Recent studies have repo rted that miR-125 a-5 p has immunomodula...Methylprednisolone pulse treatment is currently used fo r optic neuritis.It can speed visual recovery,but does not improve the ultimate visual outcomes.Recent studies have repo rted that miR-125 a-5 p has immunomodulatory effects on autoimmune diseases.However,it remains unclear whether miR-125 a-5 p has effects on optic neuritis.In this study,we used adeno-associated virus to overexpress or silence miR-125 a-5 p in mice.We found that silencing miR-125 a-5 p increased the latency of visual evoked potential and aggravated inflammation of the optic nerve.Ove rexpression of miR-125 a-5 p suppressed inflammation of the optic nerve,protected retinal ganglion cells,and increased the percentage of Treg cells.Our findings show that miR-125 a-5 p exhibits anti-inflammatory effects through promoting the diffe rentiation of Treg cells.展开更多
Cross-talk has been shown to occur between the immune system and bone metabolism pathways.In the present study,we investigated the impact of CD4^(+)CD25^(+)Foxp3^(+) regulatory T(Treg)cells on osteoclastogenesis and b...Cross-talk has been shown to occur between the immune system and bone metabolism pathways.In the present study,we investigated the impact of CD4^(+)CD25^(+)Foxp3^(+) regulatory T(Treg)cells on osteoclastogenesis and bone resorption.Treg cells that were isolated and purified from peripheral blood mononuclear cells(PBMCs)of healthy adults inhibited both the differentiation of osteoclasts(OCs)from human embryo bone marrow cells(BMCs)and the pit formation in a dose-dependent manner.In cell cocultures,the production levels of both interleukin-10(IL-10)and transforming growth factor-beta 1(TGF-β1)were proportionally upregulated as the ratio of Treg cells to BMCs was increased,and the inhibition of OC differentiation and bone resorption by Treg cells was completely reversed by anti-IL-10 and anti-TGF-β1 antibodies.Treatment of BMC and Treg cell cocultures with 17β-estradiol(E2)at concentrations between 10^(-7) and 10^(-9) mol/l suppressed OC differentiation and bone resorption more efficiently than it did in cultures of BMCs alone;this enhanced suppression occurred via the stimulation of Treg cell IL-10 and TGF-b1 expression.These data suggest that Treg cells suppress OC differentiation and bone resorption by secreting IL-10 and TGF-β1.E2 enhances the suppressive effects of Treg cells on OC differentiation and bone resorption by stimulating IL-10 and TGF-β1 secretion from these cells.Therefore,Treg cell-derived IL-10 and TGF-b1 are likely involved in the regulation of E2 on bone metabolism and represent potential therapeutic targets for the treatment of postmenopausal osteoporosis(PMO).展开更多
基金funded by the Central Hessen Research Campus,Flexi Fund,Project No.20121_1_1.
文摘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 risk factors for SAP.Stepwise linear regression could reveal an association of peak oxygen uptake(b=0.441),low-density lipoprotein(LDL)(b=0.096),and SAP(b=6.733)with mTregs and LDL(b=0.104)with rTregs.Conclusion:While at an early stage of SAP,the total proportion of Tregs gives no indication of vascular changes,this is indicated by a shift in the Treg subgroups.Factors such as serum LDL or cardiopulmonary fitness may be associated with this shift and may also be additional diagnostic indicators.This could be used to initiate lifestyle-based preventive measures at an early stage,which may have a protective effect against disease progression.
基金supported by the National Key Research and Development Program of China(Grant No.2019YFC1605000)National Natural Science Foundation of China(Grant No.31871806)the Beijing Livestock Industry Innovation Team(BAIC05-2023)。
文摘Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects and possible underlying mechanisms of MFGM on cow’s milk allergy(CMA)in aβ-lactoglobulin(BLG)-induced allergic mice model.MFGM was supplemented to allergic mice induced by BLG at a dose of 400 mg/kg body weight.Results demonstrated that MFGM alleviated food allergy symptoms,decreased serum levels of lipopolysaccharide,pro-inflammatory cytokines,immunoglobulin(Ig)E,Ig G1,and Th2 cytokines including interleukin(IL)-4,while increased serum levels of Th1 cytokines including interferon-γand regulatory T cells(Tregs)cytokines including IL-10 and transforming growth factor-β.MFGM modulated gut microbiota and enhanced intestinal barrier of BLG-allergic mice,as evidenced by decreased relative abundance of Desulfobacterota,Rikenellaceae,Lachnospiraceae,and Desulfovibrionaceae,while increased relative abundance of Bacteroidetes,Lactobacillaceae and Muribaculaceae,and enhanced expressions of tight junction proteins including Occludin,Claudin-1 and zonula occludens-1.Furthermore,MFGM increased fecal short-chain fatty acids(SCFAs)levels,which elevated G protein-coupled receptor(GPR)43 and GPR109A expressions.The increased expressions of GPR43 and GPR109A induced CD103+dendritic cells accumulation and promoted Tregs differentiation in mesenteric lymph node to a certain extent.In summary,MFGM alleviated CMA in a BLG-induced allergic mice model through enhancing intestinal barrier and promoting Tregs differentiation,which may be correlated with SCFAs-mediated activation of GPRs.These findings suggest that MFGM may be useful as a promising functional ingredient against CMA.
基金the National Natural Science Foundation of China,No.8190111624Guangxi Natural Science Foundation of China,No.2018JJB140382Guangxi University Young and Middle-Aged Teachers’Basic Scientific Research Ability Improvement Project,No.2019KY0123.
文摘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.
基金Supported by the National Natural Science Foundation of China,No.81603402,82060798,81860791the Special Fund Project for Graduate Innovation of Jiangxi University of Chinese Medicine,No.JZYC22S77+3 种基金a Special Fund Project for Graduate Innovation of Jiangxi Province,No.YC2022-s840,YC2022-B188Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program,No.CXTD22008the Young and Middle-aged Backbone Talent Project of Jiangxi Administration of Traditional Chinese Medicine,No.[2020]05Young Qhuang Scholars support Project of National Administration of Traditional Chinese Medicine,No.[2022]256.
文摘BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechanism of PTH in an AIH mouse model by determining the changes in gut microbiota structure and memory regulatory T(mTreg)cells functional levels.METHODS Following induction of the AIH mouse model induced by Concanavalin A(Con A),prophylactic administration of PTH was given for 10 d.The levels of mTreg cells were measured by flow cytometry,and intestinal microbiota was analyzed by 16S rRNA analysis,while western blotting was used to identify activation of the toll-like receptor(TLR)2,TLR4/nuclear factor-κB(NF-κB),and CXCL16/CXCR6 signaling pathways.RESULTS In the liver of mice with AIH,PTH relieved the pathological damage and reduced the numbers of T helper type 17 cells and interferon-γ,tumor necrosis factor-alpha,interleukin(IL)-1β,IL-2,IL-6,and IL-21 expression.Simultaneously,PTH stimulated the abundance of helpful bacteria,promoted activation of the TLR2 signal,which may enhance Treg/mTreg cells quantity to produce IL-10,and suppressed activation of the TLR4/NF-κB and CXCL16/CXCR6 signaling pathways.CONCLUSION PTH regulates intestinal microbiota balance and restores mTreg cells to alleviate experimental AIH,which is closely related to the TLR/CXCL16/CXCR6/NF-κB signaling pathway.
基金supported by the National Natural Science Foundation of China(81170296)
文摘BACKGROUND: Although regulatory T cells(Tregs) are key to the maintenance of immunologic homeostasis and tolerance, little is known about Treg-mediated immunosuppression in the stage of sepsis. This article aimed to review the current literature on the role of Tregs in the pathophysiology of septic response, attempting to investigate the role of Tregs in immune dysfunction during sepsis.DATA SOURCES: A literature search was conducted in January 2014 using the China National Knowledge Infrastructure and Pub Med. Articles on the role of Tregs in immune dysfunction during sepsis were identified.RESULTS: The identified articles indicated that Treg levels can be used for the assessment of the course of sepsis. The inhibition of Treg activity can promote the recovery of immune function.CONCLUSION: Since the mechanism of Tregs is complex during the sepsis, more studies are needed.
文摘Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma(HCC).Factors,including carcinogens,infection of hepatitis viruses,alcohol abuse,and non-alcoholic fatty liver disease(NAFLD),can induce HCC initiation and promote HCC progression.The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide.However,the benefit of current therapeutic options is still limited.Intrahepatic immunity plays critically important roles in HCC initiation,development,and progression.Regulatory T cells(Tregs)and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC.Therefore,targeting Tregs and blocking their mediated factors may prevent HCC progression.This review summarizes the functions of Tregs in HCC-inducing factors including alcoholic and NAFLD,liver fibrosis,cirrhosis,and viral infections.Overall,a better understanding of the role of Tregs in the development and progression of HCC provides treatment strategies for liver cancer treatment.
基金The project supported by National Natural Science Foundation of China(31570357)
文摘OBJECTIVE Experimental autoimmune encephalomyelitis(EAE),the classical animal model for multiple sclerosis(MS)is triggered by an impaired balance of T helper(Th)cells and regulatory T(Tregs)cells.Matrine(MAT),a quinolizidine alkaloid derived from the herb Radix Sophorae Flave,has been shown to ameliorate the clinical signs,inflammatory infiltration,demyelination in acute EAE rats.However,whether MAT protect from EAE by adjusting Th and Treg cells response in specific-cellular and molecular level is unknown.METHODS Herein,MAT was tested for its effects on Th1,Th2,Th17 and Treg cells in the spinal cord of EAE mice and splenocyte-extracted from EAE mice with MOG35-55-restimulated,respectively.RESULTS Our findings revealed that MAT significantly inhibit the proliferation of splenocyte,and remarkably down-regulate the differentiation of Th1/Th17 cells with decreased expressions of CD4+IFN-γ+cells and CD4+IL-17+cells in vivo and IL-17,IFN-γ,ROR-γt,T-bet in vitro,meanwhile it dramatically up-regulate the Th2/Treg cells response associated with increased levels of CD4+TGF-β+1cells and CD4+IL-10+cells in vivo and IL-4,IL-10,TGF-β1,Foxp3 and GATA3in vitro.CONCLUSION Considering the effective therapeutic effects of MAT on EAE,it′s worth to find its new values on other autoimmune diseases.
文摘Objective:To explore immunotherapy effectiveness of the CD4^(+)CD25^(+) regulatory T cells for treating female mouse with recurrent spontaneous abortion(RSA)by animal experiments.Methods:Mononuclear lymphocytes were isolated from the blood(instead of cord blood)of new-born baby of KunMing Bai mouse or BALB/c male mouse with normal birth ability(as unrelated third party blood source)by density gradient centrifuga-tion method.The CD4^(+)CD25^(+) regulatory T cells were selected by magnetic-activated cell sorting from mononuclear cells of cord blood cells.CBA/J female mouse copulated with DBA/2J male mouse was utilized as RSA animal model.Pregnant RSA mice were injected different types of lymphocytes through tail vein.Independent sample t-test was used to analyze the data from each group.Results:The proportion of CD4^(+)CD25^(+)T cells in CD4^(+)T cells was(17.49±0.60)%in CD4^(+)CD25^(+) regulatory T cells injection group,which was statistical significant higher than that of mononuclear lymphocyte injection group(14.68±0.83)%,sterile PBS group(9.54±0.85)%or no injection group(9.28±0.68)%(p<.05,t-value was 4.754,13.242 and 15.621,respec-tively).The Foxp3 relative protein expression level of CD4^(+)CD25^(+) regulatory T cells injected group was 5.85±0.45,which was also significant higher than that of mononuclear lymphocyte injection(2.86±0.54),sterile PBS group(1.08±0.16)or no injection group(1.00±0.00)(p<.05,t-value was 7.276,17.227 and 18.635,respectively).Finally,two times of CD4^(+)CD25^(+)T cell injected group at the 4 th and 8 th day had well effect for RSA mouse,and embryo sorption rate was(4.92±0.08)%,which significant lower than that of two times of mononuclear lymphocyte injected group(13.07±0.06)%,sterile PBS group(23.11±0.12)%,or no injection group(25.47±0.11)%(p<.05,t-value was-2.603,-4.012 and-4.700,respectively).Conclusions:Pregnant mouse with RSA injected CD4^(+)CD25^(+)T cells several times for immunotherapy can get better effec-tiveness than that of pregnant mouse injected traditional mononuclear cells.
文摘Objective To study the changes of lymphocyte subsets and regulatory T cells in peripheral blood of patients with acute leukemia(AL) and its clinical significance.Methods The different levels of peripheral blood lymphocyte subsets and regulatory T cells of 60 AL patients and 40 normal controls were detected with flow cytometry.Results Compared with the normal controls,the percentages of CD3+ T cells,CD4+ T cells,CD16+CD56+ NK cells and the ratio of CD4+ /CD8+ obviously decreased in newly diagnosed AL group(P <0.05),while their percentages of CD8+ T cells and CD19+ B cells significantly increased(P <0.01).The percentage of CD4+ T cells and the ratio of CD4+ /CD8+ in acute lymphoblastic leukemia(ALL) group were much lower than those in acute myelogenous leukemia(AML) group(P <0.01).Compared with these in control group,the proportions of CD4+ CD25high Treg cells and CD4+ CD25+ T cells in newly diagnosed AL group were significantly increased(P <0.01).Conclusion Cellular immune function is significantly abnormal in patients with AL.Compared with AML patients,ALL patients had poorer cellular immune function.The increased CD4 + CD25high Treg cells might be one of the important reasons of immunosuppression in AL.Detection of lymphocyte subsets and regulatory T cells is of clinical value on the evaluation of therapeutic effect and prognosis in AL patients.
基金Supported by The National Institutes of Health to Luo Y,No.RO1DK066079
文摘AIM: To investigate the role of regulatory T(Treg) cells in CD4+ T cell-mediated bladder autoimmune inflammation.METHODS: Urothelium-ovalbumin(URO-OVA)/OTII mice, a double transgenic line that expresses the membrane form of the model antigen(Ag) OVA as a self-Ag on the urothelium and the OVA-specific CD4+ T cell receptor specific for the I-Ab/OVA323-339 epitope in the periphery, were developed to provide an autoimmune environment for investigation of the role of Treg cells in bladder autoimmune inflammation. To facilitate Treg cell analysis, we further developed URO-OVAGFP-Foxp3/OT-II mice, a derived line of URO-OVA/OT-II mice that express the green fluorescent protein(GFP)-forkhead box protein P3(Foxp3) fusion protein. RESULTS: URO-OVA/OT-II mice failed to develop bladder inflammation despite the presence of autoreactive CD4+ T cells. By monitoring GFP-positive cells, bladder infiltration of CD4+ Treg cells was observed in URO-OVAGFP-Foxp3/OTII mice. The infiltrating Treg cells were functionally active and expressed Treg cell effector molecule as well as marker m RNAs including transforming growth factor-b, interleukin(IL)-10, fibrinogen-like protein 2, and glucocorticoid-induced tumor necrosis factor receptor(GITR). Studies further revealed that Treg cells from URO-OVAGFP-Foxp3/OT-II mice were suppressive and inhibited autoreactive CD4+ T cell proliferationand interferon(IFN)-g production in response to OVA Ag stimulation. Depletion of GITR-positive cells led to spontaneous development of bladder inflammation and expression of inflammatory factor m RNAs for IFN-g, IL-6, tumor necrosis factor-a and nerve growth factor in URO-OVAGFP-Foxp3/OT-II mice. CONCLUSION: Treg cells specific for bladder epithelial Ag play an important role in immunological homeostasis and the control of CD4+ T cell-mediated bladder autoimmune inflammation.
文摘Regulatory T cells(Treg cells) are a group of negative regulatory cells that include nonspecific immune regulation CD4+ T cells. Treg cells inhibit the function of other immune cells. CD_4^+ CD_(25)^+ FOXP_3^+ is a Treg cell that is co-expressed by CD_(25) and FOXP_3. The expression of Treg cells is up-regulated in the focal microenvironment and peripheral blood of patients infected with human papilloma virus(HPV). Further studies on Treg cells indicate that their potential clinical applications in the treatment of HPV infection.
基金supported by Basic Science Research Program(NRF-2020M3A9D3038435,NRF-2017R1A5A1014560)the Korea Initiative for Fostering the University of Research and Innovation Program(NRF-2020M3H1A1077095)+1 种基金through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT and Future Planning and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(grant number:HI22C2004).
文摘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 CD200^(Rhigh) 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 CD200Rhigh 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 CD200^(Rhigh) 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 CD200^(Rhigh) neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating Treg cells.
基金supported by grants from the National Natural Science Foundation of China(No.82271755,No.81871230)Peking University People's Hospital Scientific Research Development Funds(RZ 2022-06).
文摘Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.
基金the National Natural Science Foundation of China(81973221)National Natural Science Foundation for Young Scientists of China(81603647)+2 种基金the Women and Children Health Talent Project of Jiangsu Province(FRC201785)the Chinese Clinical Medicine Innovation Center of Obstetrics,Gynecology,and Reproduction in Jiangsu Province(ZX202102)the Women and Children Health Science Foundation of Jiangsu Province(F202206).
文摘Background: The absence of a safe and effective therapy for recurrent spontaneous abortion due to a maternofetal failure in immunological tolerance remains an intractable clinical obstacle for surgeons. Recently, traditional Chinese medicine has become a feasible alternative for certain diseases, including recurrent spontaneous abortion. However, because of the complex composition of the traditional Chinese medicine formula, its action mechanism remains unclear. Methods: We selected two isolated active ingredients (RAMP and baicalin) from the traditional Chinese medicine formula and used an abortion-prone CBA/J × DBA/2 model to simulate human RSA and compared the changes in fetal resorption rate, Treg cell percentage, and relevant cytokines before and after combination therapy. In addition, The mechanisms were preliminarily discussed using in vitro differentiation models. Results: In CBA/J × DBA/2 abortion-prone mice, the combination therapy resulted in a lower embryo resorption rate compared to that obtained with individual delivery of either RAMP or baicalin, thereby playing an embryo-protective role through the increase in Treg cells for the maintenance of maternal-fetal immune tolerance. In in vitro primary cell differentiation experiments, the concentration of Treg cells significantly increased from 11% to 17.9% after the combination therapy compared to that of the single administration group. Conclusion: the synergistic effects of RAMP and baicalin were responsible for Treg differentiation. The present study provides a solid basis for improving the applicability of traditional Chinese herbs in the treatment of recurrent spontaneous abortion.
基金National Natural Science Foundation of China(No.82060399)Guangxi Medical High-level Key Talents Training“139”Program Training Project(No.[2020]15),China.
文摘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.
基金upported by grants FEI 16_60 from Art.834154605(138/2012)(24/2013),SAF-2017-84978-R from MINECO(Spain)and PID2020-114396RB-I00 from Ministerio de Ciencia e Innovación(Spain)to OP and PID2021-123781OB-C22 to FJC funded by MCIN/AEI/10.13039/501100011033(Spain)and RTC-2015-3805-1 from MINECO to Inmunotek SL.LM-C and AA were recipients of FPU and UCM predoctoral fellowships,respectively.
文摘Functional Tregs play a key role in tumor development and progression,representing a major barrier to anticancer immunity.The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood.Herein,by using NMR,chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses,we demonstrate that the tumoral carbohydrate A10(Ca10),a cell-surface carbohydrate derived from Ehrlich’s tumor(ET)cells,is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs.Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming,PD-L1,IL-10,and IDO.Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features.In solid ET-bearing mice,we found positive correlations between Ca10 serum levels,tumor size and splenic Treg numbers.Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice.Remarkably,we provide evidence supporting the presence of a circulating human Ca10 counterpart(Ca10H)and show,for the first time,that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals.Of note,these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases.Collectively,we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer.The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.
基金supported by the Key Program of the National Natural Science Foundation of China(No.81930090)the National Science Foundation for Distinguished Young Scholars of China(No.81725019)the National Natural Science Foundation of China(Nos.82273571,32171104,U22A20279,81874256,and 81872556),Chongqing Natural Science Foundation(2023NSCQ-JQX0076).
文摘Although DNA mutation drives stem cell aging,how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood.Here,using a mouse model of irradiation-induced premature aging and middle-aged mice,we show that DNA mutation accumulation in hematopoietic stem cells(HSCs)during aging upregulates their surface expression of major histocompatibility complex class II(MHCII).MHCII upregulation increases the chance for recognition by bone marrow(BM)-resident regulatory T cells(Tregs),resulting in their clonal expansion and accumulation in the HSC niche.On the basis of the establishment of connexin 43(Cx43)-mediated gap junctions,BM Tregs transfer cyclic adenosine monophosphate(cAMP)to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A(PKA)signaling.Importantly,targeting the HSC–Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs.These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.
基金supported by the National Natural Science Foundation of China(No.81100581)the Beijing Bethune Charitable Foundation(No.2021).
文摘Objective Thyroid-associated ophthalmopathy(TAO)is an autoimmune disorder involving the orbital tissue.This study aimed to understand the role of regulatory T cells(Tregs)in TAO during 12-week systemic glucocorticoid(GC)treatment.Methods Thirty-two moderate-severe TAO patients with a clinical activity score(CAS)≥3/7 or with prolonged T2 relaxation time(T2RT)on at least one side of extraocular muscle(EOM)were enrolled.The percentage of the peripheral CD4+CD25(high)CD127(−/low)Tregs was analyzed using flow cytometry before and after the GC treatment.The activity and severity of TAO,T2RT,and the clinical outcomes after the GC treatment were assessed.Their correlation with the peripheral Tregs was investigated.Results There was no significant association between the baseline Treg fraction and the activity and severity of TAO or the treatment response.A significant reduction of Tregs was observed after the GC therapy merely in patients without any clinical improvement.Conclusion Treg reduction after systemic GC therapy is indicative of a poor therapeutic response.Accordingly,dynamic alterations of Tregs could help to evaluate the effectiveness of the GC treatment.
基金supported by the National Natural Science Foundation of China,No.81560162the Guangxi Natural Science Foundation of China,No.2018GXNSFAA050052(both YD)。
文摘Methylprednisolone pulse treatment is currently used fo r optic neuritis.It can speed visual recovery,but does not improve the ultimate visual outcomes.Recent studies have repo rted that miR-125 a-5 p has immunomodulatory effects on autoimmune diseases.However,it remains unclear whether miR-125 a-5 p has effects on optic neuritis.In this study,we used adeno-associated virus to overexpress or silence miR-125 a-5 p in mice.We found that silencing miR-125 a-5 p increased the latency of visual evoked potential and aggravated inflammation of the optic nerve.Ove rexpression of miR-125 a-5 p suppressed inflammation of the optic nerve,protected retinal ganglion cells,and increased the percentage of Treg cells.Our findings show that miR-125 a-5 p exhibits anti-inflammatory effects through promoting the diffe rentiation of Treg cells.
基金This work was supported by the National Key Research Program of China(No.2006CB944007,to DJL)the National Natural Science Foundation of China(No.30801502,to LW)+1 种基金the Shanghai Leading Academic Discipline Project B117(to DJL)the Program for Outstanding Medical Academic Leaders(to DJL).
文摘Cross-talk has been shown to occur between the immune system and bone metabolism pathways.In the present study,we investigated the impact of CD4^(+)CD25^(+)Foxp3^(+) regulatory T(Treg)cells on osteoclastogenesis and bone resorption.Treg cells that were isolated and purified from peripheral blood mononuclear cells(PBMCs)of healthy adults inhibited both the differentiation of osteoclasts(OCs)from human embryo bone marrow cells(BMCs)and the pit formation in a dose-dependent manner.In cell cocultures,the production levels of both interleukin-10(IL-10)and transforming growth factor-beta 1(TGF-β1)were proportionally upregulated as the ratio of Treg cells to BMCs was increased,and the inhibition of OC differentiation and bone resorption by Treg cells was completely reversed by anti-IL-10 and anti-TGF-β1 antibodies.Treatment of BMC and Treg cell cocultures with 17β-estradiol(E2)at concentrations between 10^(-7) and 10^(-9) mol/l suppressed OC differentiation and bone resorption more efficiently than it did in cultures of BMCs alone;this enhanced suppression occurred via the stimulation of Treg cell IL-10 and TGF-b1 expression.These data suggest that Treg cells suppress OC differentiation and bone resorption by secreting IL-10 and TGF-β1.E2 enhances the suppressive effects of Treg cells on OC differentiation and bone resorption by stimulating IL-10 and TGF-β1 secretion from these cells.Therefore,Treg cell-derived IL-10 and TGF-b1 are likely involved in the regulation of E2 on bone metabolism and represent potential therapeutic targets for the treatment of postmenopausal osteoporosis(PMO).
