γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be ...γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be present at different locations,including the liver,epithelial layer of the gut,the dermis and so on.Many of these cells perform specific functions in liver diseases,such as viral hepatitis,autoimmune liver diseases,non-alcoholic fatty liver disease,liver cirrhosis and liver cancers.In this review,we discuss the distribution,subsets,functions ofγδT cells and the relationship between the microbiota andγδT cells in common hepatic diseases.AsγδT cells have been used to cure hematological and solid tumors,we are interested inγδT cell-based immunotherapies to treat liver diseases.展开更多
Objective To investigate the expression and regulation of programmed cell death protein 1(PD1),B lymphocyte and T lymphocyte attenuator(BTLA)in peripheral blood of patients with non-small cell lung cancer(NSCLC);to ex...Objective To investigate the expression and regulation of programmed cell death protein 1(PD1),B lymphocyte and T lymphocyte attenuator(BTLA)in peripheral blood of patients with non-small cell lung cancer(NSCLC);to examine the correlation of the mRNA levels between PD and BTLA in NSCLC.Methods Flow cytometry was used to detect the expression of PD1 and BTLA on the surfaces of CD8^+T cells andγδ+T cells in the peripheral blood samples collected from 32 in-patients with stage IV NSCLC and 30 healthy individuals.We compared the expression of PD1 and BTLA on the surfaces ofγδ+T cells in the NSCLC patients with bone metastasis before and after the treatment of zoledronic acid.The correlations of PD1 and BTLA,as well as their ligands were analyzed using Pearson correlation analysis with the cBioPortal data platform.Results The frequency of PD1 on the surfaces of CD8^+T cells was significantly higher than that of theγδT cells in both healthy controls(t=2.324,P=0.024)and NSCLC patients(t=2.498,P=0.015).The frequency of PD1 on CD8^+T cells,rather than onγδ+T cells,was significantly upregulated in advanced NSCLC patients compared with that in healthy controls(t=4.829,P<0.001).The PD1+BTLA+γδT cells of the healthy controls were significantly lower than that of the NSCLC patients(t=2.422,P=0.0185).No differences in percentage of PD1+γδ+and BTLA+γδ+T cells were observed in 7 NSCLC patients with bone metastasis before and after zoledronic acid treatment.PD1 was positively correlated with BTLA in both lung adenocarcinoma(r=0.54;P<0.05)and lung squamous cell carcinoma(r=0.78;P<0.05).Conclusions The upregulation of co-inhibitory molecules occurs on the surfaces of both CD8^+T cells andγδT cells in advanced NSCLC,suggesting that these molecules were involved in regulating the inactivation of CD8^+T cells andγδ+T cells,immune escape and tumor invasion.展开更多
Due to the unique features of innate immune cells, the role of γδT cells in tumor immunity has gradually attracted more and more attention. Previous studies have found that γδT cells play a dual role in tumor immu...Due to the unique features of innate immune cells, the role of γδT cells in tumor immunity has gradually attracted more and more attention. Previous studies have found that γδT cells play a dual role in tumor immunology: tumor-promoting and tumor-controlling.The anti-tumor therapy of γδT cells has made remarkable success in clinical application. Especially in recent years, researchers have provided some novel effective ways such as γδT cells exosomes and adoptive chimeric antigen receptor-γδT cells immunotherapy. However, some problems remain to be solved, such as low expansion rate, poor targeting, and tumor microenvironment limiting the effectiveness of γδT immunotherapy. Traditional Chinese medicine is expected to play a positive role in the body immune-enhancing function, promoting the proliferation and activation of γδT cells, and inducing the differentiation ofγδT cells. In this review, we summarize the recent research progress and urgent problems of γδT cells in anti-tumor immunotherapy. Moreover, some new strategies of γδT cells for tumor immunotherapy were proposed.展开更多
BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome(PI-IBS).γδT cells play a crucial role in ...BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome(PI-IBS).γδT cells play a crucial role in innate and adaptive immunity.Adenosine receptors expressed on the surface ofγδT cells participate in intestinal inflammation and immunity regulation.AIM To investigate the role ofγδT cell regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS The PI-IBS mouse model has been established with Trichinella spiralis(T.spiralis)infection.The intestinal A2AR and A2AR inγδT cells were detected by immunohistochemistry,and the inflammatory cytokines were measured by western blot.The role of A2AR on the isolatedγδT cells,including proliferation,apoptosis,and cytokine production,were evaluated in vitro.Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction(RT-PCR).The animals were administered with A2AR agonist,or A2AR antagonist.Besides,γδT cells were also injected back into the animals,and the parameters described above were examined,as well as the clinical features.Furthermore,the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.RESULTS PI-IBS mice exhibited elevated ATP content and A2AR expression(P<0.05),and suppression of A2AR enhanced PI-IBS clinical characteristics,indicated by the abdominal withdrawal reflex and colon transportation test.PI-IBS was associated with an increase in intestinal T cells,and cytokine levels of interleukin-1(IL-1),IL-6,IL-17A,and interferon-α(IFN-α).Also,γδT cells expressed A2AR in vitro and generated IL-1,IL-6,IL-17A,and IFN-α,which can be controlled by A2AR agonist and antagonist.Mechanistic studies demonstrated that the A2AR antagonist improved the function ofγδT cells through the PKA/CREB/NF-κB signaling pathway.CONCLUSION Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function ofγδT cells via the PKA/CREB/NF-κB signaling pathway.展开更多
The distinct characteristics ofγδT cells determine their vital roles in the formation of local immune responses and contribute to tissue homeostasis.However,the heterogeneity ofγδT cells across tissues remains unc...The distinct characteristics ofγδT cells determine their vital roles in the formation of local immune responses and contribute to tissue homeostasis.However,the heterogeneity ofγδT cells across tissues remains unclear.By combining transcriptional and chromatin analyses with a truly unbiased fashion,we constructed a single-cell transcriptome and chromatin accessibility landscape of mouseγδT cells in the lymph,spleen,and thymus.We also revealed the heterogeneity ofγδT1 andγδT17 cells across these tissues and inferred their potential regulatory mechanisms.In the thymus,we reconstructed the developmental trajectory and gained further insights into the signature genes from the mature stage,intermediate stage,and immature stage ofγδT cells on the basis of single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing data.Notably,a novel Gzma^(+)γδT cell subset was identified with immature properties and only localized to the thymus.Finally,NR1 D1,a circadian transcription factor(TF),was validated as a key and negative regulator ofγδT17 cell differentiation by performing a combined analysis of TF motif enrichment,regulon enrichment,and Nr1 d1 knockout mice.In summary,our data represent a comprehensive mapping on the transcriptome and chromatin accessibility dynamics of mouseγδT cells,providing a valuable resource and reference for future studies onγδT cells.展开更多
The specification of theαβ/γδlineage and the maturation of medullary thymic epithelial cells(mTECs)coordinate central tolerance to self-antigens.However,the mechanisms underlying this biological process remain poo...The specification of theαβ/γδlineage and the maturation of medullary thymic epithelial cells(mTECs)coordinate central tolerance to self-antigens.However,the mechanisms underlying this biological process remain poorly clarified.Here,we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation,promoted thymic IL-17A-producingγδT-cell(Tγδ17)lineage commitment,and led to the development of fatal autoimmune hepatitis(AIH)via different mechanisms.Transfer ofγδT cells from TOX-deficient mice reproduced AIH.TOX interacted with and stabilized the TCF1 protein to maintain the balance ofγδT-cell development in thymic progenitors,and overexpression of TCF1 normalizedαβ/γδlineage specification and activation.In addition,TOX expression was downregulated inγδT cells from AIH patients and was inversely correlated with the AIH diagnostic score.Our findings suggest multifaceted roles of TOX in autoimmune control involving mTEC and Tγδ17 development and provide a potential diagnostic marker for AIH.展开更多
CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer development.However,little is known about...CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer development.However,little is known about the effects of CFTR on the differentiation and function ofγδT cells.In this study,we observed that CFTR was functionally expressed on the cell surface ofγδT cells.Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γrelease by peripheralγδT cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo.Interestingly,the molecular mechanisms underlying the regulation ofγδT cell IFN-γproduction by CFTR were either TCR dependent or related to Ca^(2+)influx.CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling.In addition,CFTR was found to modulate TCR-induced Ca^(2+)influx and membrane potential(Vm)-induced Ca^(2+)influx and subsequently regulate the calcineurin-NFATc1 signaling pathway inγδT cells.Thus,CFTR serves as a negative regulator of IFN-γproduction inγδT cells and the function of these cells in antitumor immunity.Our investigation suggests that modification of the CFTR activity ofγδT cells may be a potential immunotherapeutic strategy for cancer.展开更多
基金Supported by the National Science and Technology Major Project of China,No.2018ZX10302206 and No.2017ZX10202203-007-010。
文摘γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be present at different locations,including the liver,epithelial layer of the gut,the dermis and so on.Many of these cells perform specific functions in liver diseases,such as viral hepatitis,autoimmune liver diseases,non-alcoholic fatty liver disease,liver cirrhosis and liver cancers.In this review,we discuss the distribution,subsets,functions ofγδT cells and the relationship between the microbiota andγδT cells in common hepatic diseases.AsγδT cells have been used to cure hematological and solid tumors,we are interested inγδT cell-based immunotherapies to treat liver diseases.
基金Fund supported by the Healthcare Technology Plan of Zhejiang Provincial Health Bureau(No.2016KYB292)the Technology Plan of Science and Technology Bureau of Jiaxing,Zhejiang province(No.2016AY23054)~~
文摘Objective To investigate the expression and regulation of programmed cell death protein 1(PD1),B lymphocyte and T lymphocyte attenuator(BTLA)in peripheral blood of patients with non-small cell lung cancer(NSCLC);to examine the correlation of the mRNA levels between PD and BTLA in NSCLC.Methods Flow cytometry was used to detect the expression of PD1 and BTLA on the surfaces of CD8^+T cells andγδ+T cells in the peripheral blood samples collected from 32 in-patients with stage IV NSCLC and 30 healthy individuals.We compared the expression of PD1 and BTLA on the surfaces ofγδ+T cells in the NSCLC patients with bone metastasis before and after the treatment of zoledronic acid.The correlations of PD1 and BTLA,as well as their ligands were analyzed using Pearson correlation analysis with the cBioPortal data platform.Results The frequency of PD1 on the surfaces of CD8^+T cells was significantly higher than that of theγδT cells in both healthy controls(t=2.324,P=0.024)and NSCLC patients(t=2.498,P=0.015).The frequency of PD1 on CD8^+T cells,rather than onγδ+T cells,was significantly upregulated in advanced NSCLC patients compared with that in healthy controls(t=4.829,P<0.001).The PD1+BTLA+γδT cells of the healthy controls were significantly lower than that of the NSCLC patients(t=2.422,P=0.0185).No differences in percentage of PD1+γδ+and BTLA+γδ+T cells were observed in 7 NSCLC patients with bone metastasis before and after zoledronic acid treatment.PD1 was positively correlated with BTLA in both lung adenocarcinoma(r=0.54;P<0.05)and lung squamous cell carcinoma(r=0.78;P<0.05).Conclusions The upregulation of co-inhibitory molecules occurs on the surfaces of both CD8^+T cells andγδT cells in advanced NSCLC,suggesting that these molecules were involved in regulating the inactivation of CD8^+T cells andγδ+T cells,immune escape and tumor invasion.
文摘Due to the unique features of innate immune cells, the role of γδT cells in tumor immunity has gradually attracted more and more attention. Previous studies have found that γδT cells play a dual role in tumor immunology: tumor-promoting and tumor-controlling.The anti-tumor therapy of γδT cells has made remarkable success in clinical application. Especially in recent years, researchers have provided some novel effective ways such as γδT cells exosomes and adoptive chimeric antigen receptor-γδT cells immunotherapy. However, some problems remain to be solved, such as low expansion rate, poor targeting, and tumor microenvironment limiting the effectiveness of γδT immunotherapy. Traditional Chinese medicine is expected to play a positive role in the body immune-enhancing function, promoting the proliferation and activation of γδT cells, and inducing the differentiation ofγδT cells. In this review, we summarize the recent research progress and urgent problems of γδT cells in anti-tumor immunotherapy. Moreover, some new strategies of γδT cells for tumor immunotherapy were proposed.
基金Supported by National Natural Science Foundation of China,No.81160057,No.81860102,and No.82060102Natural Science Foundation of Hainan Province,High-level Personnel Program,No.821RC1116+1 种基金Research Project of Health Industry in Hainan Province,No.20A200066Hainan Provincial Clinical Medical Center.
文摘BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome(PI-IBS).γδT cells play a crucial role in innate and adaptive immunity.Adenosine receptors expressed on the surface ofγδT cells participate in intestinal inflammation and immunity regulation.AIM To investigate the role ofγδT cell regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS The PI-IBS mouse model has been established with Trichinella spiralis(T.spiralis)infection.The intestinal A2AR and A2AR inγδT cells were detected by immunohistochemistry,and the inflammatory cytokines were measured by western blot.The role of A2AR on the isolatedγδT cells,including proliferation,apoptosis,and cytokine production,were evaluated in vitro.Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction(RT-PCR).The animals were administered with A2AR agonist,or A2AR antagonist.Besides,γδT cells were also injected back into the animals,and the parameters described above were examined,as well as the clinical features.Furthermore,the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.RESULTS PI-IBS mice exhibited elevated ATP content and A2AR expression(P<0.05),and suppression of A2AR enhanced PI-IBS clinical characteristics,indicated by the abdominal withdrawal reflex and colon transportation test.PI-IBS was associated with an increase in intestinal T cells,and cytokine levels of interleukin-1(IL-1),IL-6,IL-17A,and interferon-α(IFN-α).Also,γδT cells expressed A2AR in vitro and generated IL-1,IL-6,IL-17A,and IFN-α,which can be controlled by A2AR agonist and antagonist.Mechanistic studies demonstrated that the A2AR antagonist improved the function ofγδT cells through the PKA/CREB/NF-κB signaling pathway.CONCLUSION Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function ofγδT cells via the PKA/CREB/NF-κB signaling pathway.
基金supported by the National Natural Science Foundation of China(31830021,32030036,32000615,and 32100695)the National Key Research and Development Program of China(2020YFA0803502)+2 种基金the 111 Project(B16021)China Postdoctoral Science Foundation(2020M683180,2019M663374,and 2020T130251)Guangdong Basic and Applied Basic Research Foundation(2020A1515111045 and 2020A1515111081)。
文摘The distinct characteristics ofγδT cells determine their vital roles in the formation of local immune responses and contribute to tissue homeostasis.However,the heterogeneity ofγδT cells across tissues remains unclear.By combining transcriptional and chromatin analyses with a truly unbiased fashion,we constructed a single-cell transcriptome and chromatin accessibility landscape of mouseγδT cells in the lymph,spleen,and thymus.We also revealed the heterogeneity ofγδT1 andγδT17 cells across these tissues and inferred their potential regulatory mechanisms.In the thymus,we reconstructed the developmental trajectory and gained further insights into the signature genes from the mature stage,intermediate stage,and immature stage ofγδT cells on the basis of single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing data.Notably,a novel Gzma^(+)γδT cell subset was identified with immature properties and only localized to the thymus.Finally,NR1 D1,a circadian transcription factor(TF),was validated as a key and negative regulator ofγδT17 cell differentiation by performing a combined analysis of TF motif enrichment,regulon enrichment,and Nr1 d1 knockout mice.In summary,our data represent a comprehensive mapping on the transcriptome and chromatin accessibility dynamics of mouseγδT cells,providing a valuable resource and reference for future studies onγδT cells.
基金This work was supported by grants from the State Key Program of the National Natural Science Foundation(81930086 and 82120108012 to BS,82073157 and 81600487 to WT)the Science and Technology Project of Jiangsu Province(BE2018603 to BS)the Postgraduate Innovative Research Program of Jiangsu Province(KYCX20_0047 to QH).
文摘The specification of theαβ/γδlineage and the maturation of medullary thymic epithelial cells(mTECs)coordinate central tolerance to self-antigens.However,the mechanisms underlying this biological process remain poorly clarified.Here,we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation,promoted thymic IL-17A-producingγδT-cell(Tγδ17)lineage commitment,and led to the development of fatal autoimmune hepatitis(AIH)via different mechanisms.Transfer ofγδT cells from TOX-deficient mice reproduced AIH.TOX interacted with and stabilized the TCF1 protein to maintain the balance ofγδT-cell development in thymic progenitors,and overexpression of TCF1 normalizedαβ/γδlineage specification and activation.In addition,TOX expression was downregulated inγδT cells from AIH patients and was inversely correlated with the AIH diagnostic score.Our findings suggest multifaceted roles of TOX in autoimmune control involving mTEC and Tγδ17 development and provide a potential diagnostic marker for AIH.
基金This work was supported by grants from the National Natural Science Foundation of China(31420103901 to Z.Y.,31830021 to Z.Y.,31970830 to J.H.,81702876 to X.L.,31500734 to Y.D.,and 31700753 to G.C.)grants from the Guangzhou Municipal Science and Technology Bureau(201904010090 to J.H.and 201906010085 to X.L.)a grant from the Health Commission of Guangdong Province(A2019520 to J.H.).
文摘CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer development.However,little is known about the effects of CFTR on the differentiation and function ofγδT cells.In this study,we observed that CFTR was functionally expressed on the cell surface ofγδT cells.Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γrelease by peripheralγδT cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo.Interestingly,the molecular mechanisms underlying the regulation ofγδT cell IFN-γproduction by CFTR were either TCR dependent or related to Ca^(2+)influx.CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling.In addition,CFTR was found to modulate TCR-induced Ca^(2+)influx and membrane potential(Vm)-induced Ca^(2+)influx and subsequently regulate the calcineurin-NFATc1 signaling pathway inγδT cells.Thus,CFTR serves as a negative regulator of IFN-γproduction inγδT cells and the function of these cells in antitumor immunity.Our investigation suggests that modification of the CFTR activity ofγδT cells may be a potential immunotherapeutic strategy for cancer.
