T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an init...T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.展开更多
Gut microbiota-derived short-chain fatty acids(SCFAs)impact asthma outcomes,highlighting the importance of understanding the disease mechanisms through the gut-lung axis.In this study,we identified that among SCFAs,bu...Gut microbiota-derived short-chain fatty acids(SCFAs)impact asthma outcomes,highlighting the importance of understanding the disease mechanisms through the gut-lung axis.In this study,we identified that among SCFAs,butyrate uniquely alleviates asthma through specifically inhibiting a newly identified pathogenic T follicular helper(Tfh)cell subset,Tfh13 cells.Tfh13 cell depletion(Il13^(Cre)/+Bcl6^(fl/fl))or adoptive transfer of Tfh13 cells in an OVA-induced asthma model conclusively demonstrated their indispensable role in driving anaphylactic IgE production and asthma pathogenesis.Mechanistically,the inhibitory function of butyrate on Tfh13 cells is mediated by the interaction between butyrate and G-protein coupled receptor 43(GPR43),leading to the suppression of p38 MAPK/NF-κB signaling in Tfh13 cells.To address the clinically observed deficiency of butyrate in patients with asthma and recapitulated in murine models,we developed a novel therapeutic strategy using a butyrate-yielding diet enriched with butylated high amylose maize starch(HAMSB).Remarkably,supplementation with HAMSB diet in murine and humanized asthma models significantly reduced Tfh13 cell frequencies and anaphylactic IgE levels,leading to significantly improved disease outcomes.Our findings not only unveil a novel mechanism underlying butyrate-mediated asthma alleviation,termed the butyrate-Tfh13-IgE axis,but also propose a clinically translatable dietary intervention strategy targeting microbial metabolites for stopping asthma.展开更多
Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T...Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T cell metabolism and function remains poorly unexplored.Here,we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid(PA)or oleic acid(OA)levels were associated with the efficacy of Vγ9Vδ2-T cell therapy.We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules,whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells.Mechanistically,we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ,which in turn induces cell pyroptosis,ultimately resulting in decreased antitumor activity.展开更多
Trichosanthin(TCS),extracted from the Chinese medicinal herb Trichosanthes kirilowi,has shown promise for the inhibition of tumor growth.However,its immunomodulatory effect on tumor–host interaction remains unknown.I...Trichosanthin(TCS),extracted from the Chinese medicinal herb Trichosanthes kirilowi,has shown promise for the inhibition of tumor growth.However,its immunomodulatory effect on tumor–host interaction remains unknown.In this study,we focused on the effect of TCS on murine anti-tumor immune response in the 3LL Lewis lung carcinoma tumor model and explored the possible molecular pathways involved.In addition to inhibiting cell proliferation and inducing apoptosis in the 3LL tumor,TCS retarded tumor growth and prolonged mouse survival more significantly in C57BL/6 immunocompetent mice than in nude mice.This reflected the fact that the host immune system was involved in tumor eradication.Using FACS analysis,we found that TCS increased the percentage of effector T cells,particularly Interferon-gamma(IFN-c)producing CD41 and CD81 T cells from tumor-bearing mice.TCS also promoted the vigorous proliferation of antigen-specific effector T cells,markedly increased Th1 cytokine secretion and elicited more memory T cells in tumor-bearing mice,consequently enhancing the anti-tumor response and inducing immune protection.Furthermore,we found that TCS upregulated the expression of tumor suppressor in lung cancer 1(TSLC1)in 3LL tumor cells and the expression of its ligand,class I-restricted T cell-associated molecule(CRTAM),in effector T cells.Blocking TSLC1 expression with small interfering RNA(siRNA)significantly eliminated the effects of TCS on the proliferation and cytokine secretion of effector T cells,suggesting that TCS enhances anti-tumor immune response at least partially by boosting the interaction between TSLC1 and CRTAM.Collectively,our data demonstrate that TCS not only affects tumor cells directly,but also enhances anti-tumor immunity via the interaction between TSLC1 and CRTAM.These findings may lead to the development of a novel approach for tumor regression.展开更多
The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown.Using a Pseudomonas aeruginosa-induced pneumonia model,we reported that IL-10-producing B cells(IL...The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown.Using a Pseudomonas aeruginosa-induced pneumonia model,we reported that IL-10-producing B cells(IL-10+B cells)play a key role in spontaneously resolving infection-mediated inflammation.Accumulated cytosolic reactive oxygen species(ROS)during inflammation were shown to drive IL-10+B-cell generation by remodeling one-carbon metabolism.Depletion of the enzyme serine hydroxymethyltransferase 1(Shmt1)led to inadequate one-carbon metabolism and decreased IL-10+B-cell production.Furthermore,increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine(SAM),altering histone H3 lysine 4 methylation(H3K4me)at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells.Therefore,the one-carbon metabolism-associated compound ethacrynic acid(EA)was screened and found to potentially treat infectious pneumonia by boosting IL-10+B-cell generation.Overall,these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.展开更多
Bladder cancer(BLCA)remains a difficult malignancy to manage because of its high recurrence,intense follow-up,and invasive diagnostic and treatment techniques.Immune checkpoint inhibitors(ICIs)have forged a new direct...Bladder cancer(BLCA)remains a difficult malignancy to manage because of its high recurrence,intense follow-up,and invasive diagnostic and treatment techniques.Immune checkpoint inhibitors(ICIs)have forged a new direction for the treatment of BLCA,but it is currently challenging to predict whether an individual patient will be sensitive to ICIs.We collected 43 urine/tumor samples from BLCA patients for primary bladder cancer cells(BCCs)culturing using our previously reported BCC culture platform.We used flow cytometry(FCM)to measure the expression levels of Programmed Death-Ligand 1(PD-L1)on BCCs before and after interferon-gamma(IFN-γ)treatment and found that PD-L1 expression and the sensitivities to IFN-γvaried among patients.RNA-sequencing,western blotting,and programmed death-1(PD-1)binding assays confirmed that the BCC FCM-based PD-L1 detection platform(BC-PD-L1)was reliable and was not hindered by the glycosylation of PD-L1.In the subsequent retrospective study,we found that IFN-γ-stimulated PD-L1(sPD-L1)expression on BCCs detected by BC-PD-L1 could predict the prognosis of BLCA patients.Importantly,the prognostic value was similar or even better in urine-derived BC-PD-L1(UBC-PD-L1).Transcriptome analysis showed that BCCs with high sPD-L1 tended to enrich genes associated with the collagen-containing extracellular matrix,cell–cell adhesion,and positive regulation of the immune system.In addition,the UBC-PD-L1 also exhibited predictive value for ICI response in BLCA patients.In conclusion,as a novel personalized urine-detection method,UBC-PD-L1 may provide a rapid,accurate,and non-invasive tool for monitoring tumor progression,predicting therapeutic responses,and helping improve BLCA clinical treatment in future.展开更多
基金supported by the National Major Scientic Research Program of China(Grant No.2011CB910404)the National Nature Science Foundation of China(Grant Nos.61227017,31400772 and 81273215)+3 种基金the National Science Fund for Distinguished Young Scholars(Grant No.61425006)the grants of the Project for Laureate of Taishan Scholar(Grant No.ts201511075)the Innovation Project of Shandong Academy of Medical Sciences,the Projects of medical and health technology development program in Shandong province(No.2015WS0194)the science and technology program from Shandong Academy of Medical Sciences(No.2015-25).
文摘T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.
基金supported by the General Program of the National Natural Science Foundation of China(81971493)the Science Fund for Creative Research Groups of the National Natural Science Foundation of China(82121002)+1 种基金the Major Program of National Natural Science Foundation of China(82130050,82330053)the Innovative Research Team of High-level Local Universities in Shanghai。
文摘Gut microbiota-derived short-chain fatty acids(SCFAs)impact asthma outcomes,highlighting the importance of understanding the disease mechanisms through the gut-lung axis.In this study,we identified that among SCFAs,butyrate uniquely alleviates asthma through specifically inhibiting a newly identified pathogenic T follicular helper(Tfh)cell subset,Tfh13 cells.Tfh13 cell depletion(Il13^(Cre)/+Bcl6^(fl/fl))or adoptive transfer of Tfh13 cells in an OVA-induced asthma model conclusively demonstrated their indispensable role in driving anaphylactic IgE production and asthma pathogenesis.Mechanistically,the inhibitory function of butyrate on Tfh13 cells is mediated by the interaction between butyrate and G-protein coupled receptor 43(GPR43),leading to the suppression of p38 MAPK/NF-κB signaling in Tfh13 cells.To address the clinically observed deficiency of butyrate in patients with asthma and recapitulated in murine models,we developed a novel therapeutic strategy using a butyrate-yielding diet enriched with butylated high amylose maize starch(HAMSB).Remarkably,supplementation with HAMSB diet in murine and humanized asthma models significantly reduced Tfh13 cell frequencies and anaphylactic IgE levels,leading to significantly improved disease outcomes.Our findings not only unveil a novel mechanism underlying butyrate-mediated asthma alleviation,termed the butyrate-Tfh13-IgE axis,but also propose a clinically translatable dietary intervention strategy targeting microbial metabolites for stopping asthma.
基金supported in part by the General Research Fund(17122519,17126317,1712222217119123,17106624)+5 种基金the Collaborative Research Fund(C4008-23W)Research Grants Council of Hong Kongthe Health and Medical Research Fund,Food and Health Bureau(18192021)Hong Kong SAR GovernmentSeed Funding for Strategic Interdisciplinary Research Scheme,University of Hong Kong Hong Kong SAR,ChinaShenzhen Institute of Synthetic Biology Scientific Research Program(ZTXM20214004),Shenzhen,China.
文摘Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T cell metabolism and function remains poorly unexplored.Here,we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid(PA)or oleic acid(OA)levels were associated with the efficacy of Vγ9Vδ2-T cell therapy.We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules,whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells.Mechanistically,we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ,which in turn induces cell pyroptosis,ultimately resulting in decreased antitumor activity.
基金the National Key Technologies R&D Program of China during the Eleventh Five-Year Plan Period(2009ZX10004-104 and 2009ZX09301-011)National Science Foundation of China(30872378 and 81072408)the Science and Technology Commission of Shanghai Municipality(10JC1401100)in China and National 973 Project(2010CB912603 and 2011CB910400)in China.We thank the editors of Editage Company for professional editing of the article.
文摘Trichosanthin(TCS),extracted from the Chinese medicinal herb Trichosanthes kirilowi,has shown promise for the inhibition of tumor growth.However,its immunomodulatory effect on tumor–host interaction remains unknown.In this study,we focused on the effect of TCS on murine anti-tumor immune response in the 3LL Lewis lung carcinoma tumor model and explored the possible molecular pathways involved.In addition to inhibiting cell proliferation and inducing apoptosis in the 3LL tumor,TCS retarded tumor growth and prolonged mouse survival more significantly in C57BL/6 immunocompetent mice than in nude mice.This reflected the fact that the host immune system was involved in tumor eradication.Using FACS analysis,we found that TCS increased the percentage of effector T cells,particularly Interferon-gamma(IFN-c)producing CD41 and CD81 T cells from tumor-bearing mice.TCS also promoted the vigorous proliferation of antigen-specific effector T cells,markedly increased Th1 cytokine secretion and elicited more memory T cells in tumor-bearing mice,consequently enhancing the anti-tumor response and inducing immune protection.Furthermore,we found that TCS upregulated the expression of tumor suppressor in lung cancer 1(TSLC1)in 3LL tumor cells and the expression of its ligand,class I-restricted T cell-associated molecule(CRTAM),in effector T cells.Blocking TSLC1 expression with small interfering RNA(siRNA)significantly eliminated the effects of TCS on the proliferation and cytokine secretion of effector T cells,suggesting that TCS enhances anti-tumor immune response at least partially by boosting the interaction between TSLC1 and CRTAM.Collectively,our data demonstrate that TCS not only affects tumor cells directly,but also enhances anti-tumor immunity via the interaction between TSLC1 and CRTAM.These findings may lead to the development of a novel approach for tumor regression.
基金supported by the General Program of the National Natural Science Foundation of China(81971493,81771736)the Science Fund for Creative Research Groups of the National Natural Science Foundation of China(82121002)+2 种基金Major Program of National Natural Science Foundation of China(821300501,82330053)Shanghai Rising-Star Program(20QA1407900)Innovative Research Team of High-level Local Universities in Shanghai.
文摘The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown.Using a Pseudomonas aeruginosa-induced pneumonia model,we reported that IL-10-producing B cells(IL-10+B cells)play a key role in spontaneously resolving infection-mediated inflammation.Accumulated cytosolic reactive oxygen species(ROS)during inflammation were shown to drive IL-10+B-cell generation by remodeling one-carbon metabolism.Depletion of the enzyme serine hydroxymethyltransferase 1(Shmt1)led to inadequate one-carbon metabolism and decreased IL-10+B-cell production.Furthermore,increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine(SAM),altering histone H3 lysine 4 methylation(H3K4me)at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells.Therefore,the one-carbon metabolism-associated compound ethacrynic acid(EA)was screened and found to potentially treat infectious pneumonia by boosting IL-10+B-cell generation.Overall,these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.
基金supported by the National Natural Science Foundation of China(No.82073413 to S.J.)the Clinical and Research Fund of Wu Jieping Medical Foundation(No.320.6750.2020-01-12 to S.J.)+1 种基金the National Natural Science Foundation of China(No.22137002 to Y.D.)the China Postdoctoral Science Foundation(No.2020TQ0068 to J.W.).
文摘Bladder cancer(BLCA)remains a difficult malignancy to manage because of its high recurrence,intense follow-up,and invasive diagnostic and treatment techniques.Immune checkpoint inhibitors(ICIs)have forged a new direction for the treatment of BLCA,but it is currently challenging to predict whether an individual patient will be sensitive to ICIs.We collected 43 urine/tumor samples from BLCA patients for primary bladder cancer cells(BCCs)culturing using our previously reported BCC culture platform.We used flow cytometry(FCM)to measure the expression levels of Programmed Death-Ligand 1(PD-L1)on BCCs before and after interferon-gamma(IFN-γ)treatment and found that PD-L1 expression and the sensitivities to IFN-γvaried among patients.RNA-sequencing,western blotting,and programmed death-1(PD-1)binding assays confirmed that the BCC FCM-based PD-L1 detection platform(BC-PD-L1)was reliable and was not hindered by the glycosylation of PD-L1.In the subsequent retrospective study,we found that IFN-γ-stimulated PD-L1(sPD-L1)expression on BCCs detected by BC-PD-L1 could predict the prognosis of BLCA patients.Importantly,the prognostic value was similar or even better in urine-derived BC-PD-L1(UBC-PD-L1).Transcriptome analysis showed that BCCs with high sPD-L1 tended to enrich genes associated with the collagen-containing extracellular matrix,cell–cell adhesion,and positive regulation of the immune system.In addition,the UBC-PD-L1 also exhibited predictive value for ICI response in BLCA patients.In conclusion,as a novel personalized urine-detection method,UBC-PD-L1 may provide a rapid,accurate,and non-invasive tool for monitoring tumor progression,predicting therapeutic responses,and helping improve BLCA clinical treatment in future.
