Objective:To investigate the changes of Mg^(2+) levels in serum and peripheral blood mononuclear cells(PBMCs)of patients with COVID-19 and its effects on the functions of CD8^(+)T lymphocytes and NK cells.Methods:A to...Objective:To investigate the changes of Mg^(2+) levels in serum and peripheral blood mononuclear cells(PBMCs)of patients with COVID-19 and its effects on the functions of CD8^(+)T lymphocytes and NK cells.Methods:A total of 165 COVID-19 patients hospitalized in Ezhou Central Hospital from January 20 to February 20,2020 were divided into mild/common group(98 cases)and severe/critical group(67 cases).At the same time,34 healthy persons were selected as the control group.Peripheral blood was collected and PBMCs were isolated,the level of Mg^(2+) in serum and PBMCs was detected.The subsets of CD8^(+)T lymphocytes and NK cell and the expression levels of their surface inhibitory molecular PD-1 and activator molecular NKG2D were detected by flow cytometry.The correlation between Mg^(2+) concentration and the expression levels of PD-1 and NKG2D was also analyzed.Results:Compared with the control group,the concentration of Mg^(2+) in serum and PBMCs,the counts of CD8^(+)T lymphocytes and NK cell in patients with mild/common and severe/critical groups were significantly reduced(P<0.05),while the expression level of surface inhibitory molecular PD-1 were significantly increased(P<0.05),while the expression level of the activation molecule NKG2D were significantly decreased(P<0.05).However,the changes of the above indicators in patients with severe/critical group were greater than those in the mild/common group(P<0.05).In addition,the Mg^(2+) concentration in COVID-19 patients was negatively correlated with the expression level of PD-1 on CD8^(+)T lymphocytes and NK cells(P<0.05),and positively correlated with the expression levels of NKG2D(P<0.05).Conclusion:The concentration of Mg^(2+) in the serum and PBMCs of COVID-19 patients is significantly reduced,which may cause the function of CD8^(+)T lymphocytes and NK cells to be inhibited.展开更多
Background The cause of late-onset hemorrhagic cystitis （LOHC） after allogeneic hematopoietic stem cell transplantation （allo-HSCT） remains obscure. In clinical practice, some LOHC patients respond to immunosuppre...Background The cause of late-onset hemorrhagic cystitis （LOHC） after allogeneic hematopoietic stem cell transplantation （allo-HSCT） remains obscure. In clinical practice, some LOHC patients respond to immunosuppression.The aim of this study was to determine the immune pathogenesis of LOHC post allo-HSCT.Methods With the diagnosis of LOHC, patients were given initial treatment consisting of fluid hydration, alkalization and forced diuresis, and empirical anti-viral therapy for 10-14 days or until a week after the virus became negative. The nonresponders were applied corticosteroid. Seven to ten days later, patients＇ response was evaluated. Along with treatment, CD19^＋ B lymphocyte subsets were measured at various study points.Results From October 2009 to March 2010, we found 28 cases of LOHC occurred in 25 patients who underwent allo-HSCT in our hospital. Except that three cases were not treated according to the protocol, the other 25 cases were divided into three groups： anti-virus responders （Group A, n=6）, corticosteroid responders （Group B1, n=16）,corticosteroid and anti-virus nonresponders （Group C, n=3） according to their clinical response. Percentages of CD19^＋CD5^＋ B lymphocytes were not significantly different among three groups at onset of LOCH. However, in Group B1after the first anti-virus phase, percentages of CD19^＋CD5^＋ lymphocytes significantly increased comparing with those at onset （P=0.022）, and then significantly decreased at PR （P=0.003） and CR （P=0.002） with corticosteroid treatment. But significant change was not observed in Groups A and C.Conclusion The immune etiology seems to be involved in the development of LOHC and the proportion of CD19^＋CD5^＋lymphocytes may serve as a cellular biomarker to predict the response to corticosteroid in LOHC展开更多
Since the outbreak of the coronavirus disease 2019(COVID-19)epidemic in 2019,the public health system has faced enormous challenges.Tracking the individuals who test positive for severe acute respiratory syndrome coro...Since the outbreak of the coronavirus disease 2019(COVID-19)epidemic in 2019,the public health system has faced enormous challenges.Tracking the individuals who test positive for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a key step for interrupting chains of transmission of SARS-CoV-2 and reducing COVID-19-associated mortality.With the increasing of asymptomatic infections,it is difficult to track asymptomatic infections through epidemiological surveys and virus whole-genome sequencing.However,due to the cross-reactivity of neutralizing antibodies produced by multiple virus subtypes,neutralizing antibody detection cannot be used to determine whether an individual has a history of infection with a specific subtype of SARS-CoV-2.We recruited 4 human leukocyte antigen A2(HLA-A2)infections,15 individuals who received three doses of inactivated vaccines,and 30 breakthrough infections after vaccination and discussed a case-tracking approach to detect epitope-specific CD8^(+)T cells in the peripheral blood of close contacts,including accurate HLA typing based on ribonucleic acid(RNA)-sequencing and flow cytometry data and the comparison and characterization of SARS-CoV-2 HLA-A2 and HLA-A24 epitope-specific CD8^(+)T cells.From individuals who received three doses of inactivated vaccine,we observed that the CD8^(+)T cell specificity for ancestral epitopes was significantly higher than for mutated epitopes,and the fold change of CD8^(+)T cells corresponding to mutated epitopes relative to ancestral epitopes was less than 1.The enzyme-linked immunospot(ELISpot)results further validate this result.This study forms a“method for understanding the infection history of SARS-CoV-2 subtypes based on the proportion of epitope-specific CD8^(+)T cells in the peripheral blood of subjects”,covering up to 46%of the population,including HLA-A2+and HLA-A24+donors,providing a novel method for SARS-CoV-2 infected case tracing.展开更多
Decidual natural killer （dNK） cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early preg...Decidual natural killer （dNK） cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnancy. However, the mechanism for how the dNK cells play such important roles in successful pregnancy remains undefined. Here, we identified a subtype of dNK cells characterized as having a CD3-CD56^brightCD25^＋ phenotype. We found that CD56^brightCD25^＋ NK cells preferentially localize to the maternal/fetal interface during early human pregnancy. CD25^＋ dNK cells account for approximately 75% of CD25-expressing decidual immune cells （DICs）. However, less than 5% of CD25-positive peripheral blood mononuclear cells are CD25^＋ NK cells. Furthermore, CD25^＋ and CD25^- dNK cells exhibit distinct phenotypes： CD25^＋ dNK cells display a more activated phenotype and greater cytokine-secreting capacity. Interestingly, coculture of peripheral NK （pNK） cells with primary trophoblasts upregulates the percentage of CD25-expressing pNK cells, resulting in increased expression of activation markers and cytokine production by pNK cells. In addition, we demonstrated that the CXCL12/CXCR4 axis is crucial for the recruitment of CD25^＋ dNK cells and contributes to the accumulation of CD3^-CD56^brightCD25^＋ dNK cells at the maternal/fetal interface. Thus, our data reveal that the crosstalk between trophoblasts and pNK cells leads to the accumulation of CD3^-CD56^brightCD25^＋ dNK cells, which exert a regulating effect at the maternal/fetal interface.展开更多
In addition to CD4^(+)T cells and neutralizing antibodies,CD8^(+)T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019(COVID-19),an ongoing pandemic disease.In ...In addition to CD4^(+)T cells and neutralizing antibodies,CD8^(+)T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019(COVID-19),an ongoing pandemic disease.In patients with COVID-19,CD8^(+)T cells exhibiting activated phenotypes are commonly observed,although the absolute number of CD8^(+)T cells is decreased.In addition,several studies have reported an upregulation of inhibitory immune checkpoint receptors,such as PD-1,and the expression of exhaustion-associated gene signatures in CD8^(+)T cells from patients with COVID-19.However,whether CD8^(+)T cells are truly exhausted during COVID-19 has been a controversial issue.In the present review,we summarize the current understanding of CD8^(+)T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8^(+)T cells in the context of activation and exhaustion.We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8^(+)T cells and discuss long-term SARS-CoV-2-specific CD8^(+)T-cell memory.展开更多
Signal transducers and activators of transcription 5(Stat5)is known to engage in regulating the differentiation and effector function of various subsets of T helper cells.However,how Stat5 regulates the antitumor acti...Signal transducers and activators of transcription 5(Stat5)is known to engage in regulating the differentiation and effector function of various subsets of T helper cells.However,how Stat5 regulates the antitumor activity of tumor-infiltrating CD4^(+)T cells is largely unknown.Here,we showed that mice with specific deletion of Stat5 in CD4^(+)T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4^(+)tumor-infiltrating lymphocytes(TILs)remolding.Especially,we confirmed that Stat5-deficient CD4^(+)naïve T cells were prone to polarization of two subtypes of Th17 cells:IFN-γ^(+)and IFN-γ^(-)Th17 cells,which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells.Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma.This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients.展开更多
卵巢上皮性癌（卵巢癌）的治疗方法包括手术结合化疗或放疗，但以上方法均未能使晚期卵巢癌患者约30％的5年生存率得以改善，使卵巢癌成为妇科肿瘤中的治疗难点，促使我们寻找新的治疗手段。近年来，免疫治疗成为肿瘤治疗的新辅助方法...卵巢上皮性癌（卵巢癌）的治疗方法包括手术结合化疗或放疗，但以上方法均未能使晚期卵巢癌患者约30％的5年生存率得以改善，使卵巢癌成为妇科肿瘤中的治疗难点，促使我们寻找新的治疗手段。近年来，免疫治疗成为肿瘤治疗的新辅助方法，显示了一定的治疗效果，其中CD4^＋CD25^＋去调节性T淋巴细胞（regulatory T cells，Tr细胞）成为研究热点，并逐渐从基础研究过渡到临床研究，本文就其在卵巢癌中的研究进展进行综述。展开更多
Autoreactive CD8^(+)T cells,which play an indispensable role inβcell destruction,represent an emerging target for the prevention of type 1 diabetes(T1D).Altered peptide ligands(APLs)can efficiently induce antigen-spe...Autoreactive CD8^(+)T cells,which play an indispensable role inβcell destruction,represent an emerging target for the prevention of type 1 diabetes(T1D).Altered peptide ligands(APLs)can efficiently induce antigen-specific T cells anergy,apoptosis or shifts in the immune response.Here,we found that HLA-A*0201-restricted CD8^(+)T cell responses against a primaryβ-cell autoantigen insulin epitope InsB15–14 were present in both NOD.β2m null.HHD NOD mice and T1D patients.We generated several APL candidates for InsB15–14 by residue substitution at the p6 position.Only H6F exhibited an inhibitory effect on mInsB1_(5–14)-specific CD8^(+)T cell responses in vitro.H6F treatment significantly reduced the T1D incidence,which was accompanied by diminished autoreactive CD8^(+)T cell responses to mInsB15-14,inhibited infiltration of CD8^(+)and CD4^(+)T cells in the pancreas and reduced pro-inflammatory cytokine production in pancreatic and splenic T cells in NOD.β2m^(null).HHD mice.Mechanistically,H6F treatment significantly augmented a tiny portion of CD8^(+)CD25^(+)Foxp3^(+)T cells in the spleen and especially in the pancreas.This subset exhibited typical Treg phenotypes and required peptide-specific restimulation to exert immunosuppressive activity.Therefore,this APL H6F may be a promising candidate with potential clinical application value for antigen-specific prevention of T1D.展开更多
Berberine(BBR)as one of the most effective natural products has been increasingly used to treat various chronic diseases due to its immunosuppressive/tolerogenic activities.However,it is unknown if BBR can be applied ...Berberine(BBR)as one of the most effective natural products has been increasingly used to treat various chronic diseases due to its immunosuppressive/tolerogenic activities.However,it is unknown if BBR can be applied without abrogating the efforts of vaccination.Here we show that priming of CD8^(+)T cells in the presence of BBR lead to improved central memory formation(Tcm)with substantially reduced effector proliferation,primarily orchestrated through activation of AMPK and Stat5.Tcm derived from vaccinated mice fed with BBR were able to adoptively transfer protective immunity to naIve recipients.Vaccination of BBR-fed mice conferred better memory protection against infection without losing immediate effector efficacy,suggesting appreciable benefits from using BBR in vaccination.Thus,our study may help to lay the groundwork for mechanistic understanding of the immunomodulatory effects of natural products and their potential use as adjuvant that allows the design of novel vaccines with more desirable properties.展开更多
Background and Aims:Overexpression of IGF2BP3 is associated with the prognosis of hepatocellular carcinoma(HCC).However,its role in regulating tumor immune microenvironment(TME)is not well characterized.Here,we invest...Background and Aims:Overexpression of IGF2BP3 is associated with the prognosis of hepatocellular carcinoma(HCC).However,its role in regulating tumor immune microenvironment(TME)is not well characterized.Here,we investigated the effects of IGF2BP3 on macrophages and CD8^(+)T cells within the TME of HCC.Methods:The relationship between IGF2BP3 and immune cell infiltration was analyzed using online bioinformatics tools.Knockout of IGF2BP3 in mouse hepatoma cell line Hepa1-6 was established using CRISPR/Cas9 technology.In vitro cell coculture and subcutaneously implanted hepatoma mice model were used to explore the effects of IGF2BP3 on immune cells.Expression of CCL50l transforming growth factor beta 1(TGF-β1)was detected with quantitative real-time polymerase chain reaction,western blotting,and enzyme-linked immunosorbent assay.The binding of IGF2BP3 and its target RNA was verified by trimolecular fluorescence complementation system and RNA immunoprecipitation followed by quantitative or semiquantitative polymerase chain reaction.Results:IGF2BP3 expression was elevated in HCC and was positively correlated with macrophage infiltration.Patients with higher IGF2BP3 expression and lower macrophage infiltration had a better survival rate.We found that IGF2BP3 could bind to the mRNA of CCL5 or TGF-β1,increasing their expression,and inducing macrophage infiltration and M2 polarization while inhibiting the activation of CD8^(+)T cells.Furthermore,inhibition of IGF2BP3 combined with anti-CD47 antibody treatment significantly suppressed the growth of hepatoma in Hepa1-6 xenograft tu-mor mice.Conclusions:IGF2BP3 promoted the infiltration and M2-polarization of macrophages and suppressed CD8^(+)T activation by enhancing CCL5 and TGF-β1 expression,which facilitated the progression of Hepa1-6 xenograft tumor.展开更多
文摘Objective:To investigate the changes of Mg^(2+) levels in serum and peripheral blood mononuclear cells(PBMCs)of patients with COVID-19 and its effects on the functions of CD8^(+)T lymphocytes and NK cells.Methods:A total of 165 COVID-19 patients hospitalized in Ezhou Central Hospital from January 20 to February 20,2020 were divided into mild/common group(98 cases)and severe/critical group(67 cases).At the same time,34 healthy persons were selected as the control group.Peripheral blood was collected and PBMCs were isolated,the level of Mg^(2+) in serum and PBMCs was detected.The subsets of CD8^(+)T lymphocytes and NK cell and the expression levels of their surface inhibitory molecular PD-1 and activator molecular NKG2D were detected by flow cytometry.The correlation between Mg^(2+) concentration and the expression levels of PD-1 and NKG2D was also analyzed.Results:Compared with the control group,the concentration of Mg^(2+) in serum and PBMCs,the counts of CD8^(+)T lymphocytes and NK cell in patients with mild/common and severe/critical groups were significantly reduced(P<0.05),while the expression level of surface inhibitory molecular PD-1 were significantly increased(P<0.05),while the expression level of the activation molecule NKG2D were significantly decreased(P<0.05).However,the changes of the above indicators in patients with severe/critical group were greater than those in the mild/common group(P<0.05).In addition,the Mg^(2+) concentration in COVID-19 patients was negatively correlated with the expression level of PD-1 on CD8^(+)T lymphocytes and NK cells(P<0.05),and positively correlated with the expression levels of NKG2D(P<0.05).Conclusion:The concentration of Mg^(2+) in the serum and PBMCs of COVID-19 patients is significantly reduced,which may cause the function of CD8^(+)T lymphocytes and NK cells to be inhibited.
文摘Background The cause of late-onset hemorrhagic cystitis （LOHC） after allogeneic hematopoietic stem cell transplantation （allo-HSCT） remains obscure. In clinical practice, some LOHC patients respond to immunosuppression.The aim of this study was to determine the immune pathogenesis of LOHC post allo-HSCT.Methods With the diagnosis of LOHC, patients were given initial treatment consisting of fluid hydration, alkalization and forced diuresis, and empirical anti-viral therapy for 10-14 days or until a week after the virus became negative. The nonresponders were applied corticosteroid. Seven to ten days later, patients＇ response was evaluated. Along with treatment, CD19^＋ B lymphocyte subsets were measured at various study points.Results From October 2009 to March 2010, we found 28 cases of LOHC occurred in 25 patients who underwent allo-HSCT in our hospital. Except that three cases were not treated according to the protocol, the other 25 cases were divided into three groups： anti-virus responders （Group A, n=6）, corticosteroid responders （Group B1, n=16）,corticosteroid and anti-virus nonresponders （Group C, n=3） according to their clinical response. Percentages of CD19^＋CD5^＋ B lymphocytes were not significantly different among three groups at onset of LOCH. However, in Group B1after the first anti-virus phase, percentages of CD19^＋CD5^＋ lymphocytes significantly increased comparing with those at onset （P=0.022）, and then significantly decreased at PR （P=0.003） and CR （P=0.002） with corticosteroid treatment. But significant change was not observed in Groups A and C.Conclusion The immune etiology seems to be involved in the development of LOHC and the proportion of CD19^＋CD5^＋lymphocytes may serve as a cellular biomarker to predict the response to corticosteroid in LOHC
基金the Key Project of Shenzhen Science and Technology Innovation Commission(JCYJ20210324115411030)Natural Science Foundation of China(92169102)+10 种基金R&D Program of Guangzhou Laboratory(SRPG22-006)Sanming Project of Medicine in Shenzhen(SZSM202211023)GuangDong Basic and Applied Basic Research Foundation(2022B1515120043)the Open Project Fund of Guangdong Provincial People’s Hospital(YKY-KF202208)National Natural Science Foundation of China(81902097)Funding by Science and Technology Projects in Guangzhou(SL2023A04J01160)the Guangdong Basic andApplied Basic Research Foundation(2023A1515140117)the fellowship of China Postdoctoral Science Foundation(2023TQ0136,2023M741379)supported by grants from the National Key Research and Development Plan(2023YFE0118700,2021YFC2301604)the Fundamental Research Funds for the Central Q4 Universities(21623406).
文摘Since the outbreak of the coronavirus disease 2019(COVID-19)epidemic in 2019,the public health system has faced enormous challenges.Tracking the individuals who test positive for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a key step for interrupting chains of transmission of SARS-CoV-2 and reducing COVID-19-associated mortality.With the increasing of asymptomatic infections,it is difficult to track asymptomatic infections through epidemiological surveys and virus whole-genome sequencing.However,due to the cross-reactivity of neutralizing antibodies produced by multiple virus subtypes,neutralizing antibody detection cannot be used to determine whether an individual has a history of infection with a specific subtype of SARS-CoV-2.We recruited 4 human leukocyte antigen A2(HLA-A2)infections,15 individuals who received three doses of inactivated vaccines,and 30 breakthrough infections after vaccination and discussed a case-tracking approach to detect epitope-specific CD8^(+)T cells in the peripheral blood of close contacts,including accurate HLA typing based on ribonucleic acid(RNA)-sequencing and flow cytometry data and the comparison and characterization of SARS-CoV-2 HLA-A2 and HLA-A24 epitope-specific CD8^(+)T cells.From individuals who received three doses of inactivated vaccine,we observed that the CD8^(+)T cell specificity for ancestral epitopes was significantly higher than for mutated epitopes,and the fold change of CD8^(+)T cells corresponding to mutated epitopes relative to ancestral epitopes was less than 1.The enzyme-linked immunospot(ELISpot)results further validate this result.This study forms a“method for understanding the infection history of SARS-CoV-2 subtypes based on the proportion of epitope-specific CD8^(+)T cells in the peripheral blood of subjects”,covering up to 46%of the population,including HLA-A2+and HLA-A24+donors,providing a novel method for SARS-CoV-2 infected case tracing.
基金This work was supported by the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission （STCSM） （12JC1401600 to DJL）, the Key Project of Shanghai Municipal Education Commission （MECSM） （14ZZ013 to MRD） and the Nature Science Foundation from National Nature Science Foundation of China （NSFC） （NSFC31270969 to DJL NSFC81070537, NSFC31171437 and NSFC81370770 to MRD+1 种基金 NSFC31300751 to HLP NSFC81370730 to QF）.
文摘Decidual natural killer （dNK） cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnancy. However, the mechanism for how the dNK cells play such important roles in successful pregnancy remains undefined. Here, we identified a subtype of dNK cells characterized as having a CD3-CD56^brightCD25^＋ phenotype. We found that CD56^brightCD25^＋ NK cells preferentially localize to the maternal/fetal interface during early human pregnancy. CD25^＋ dNK cells account for approximately 75% of CD25-expressing decidual immune cells （DICs）. However, less than 5% of CD25-positive peripheral blood mononuclear cells are CD25^＋ NK cells. Furthermore, CD25^＋ and CD25^- dNK cells exhibit distinct phenotypes： CD25^＋ dNK cells display a more activated phenotype and greater cytokine-secreting capacity. Interestingly, coculture of peripheral NK （pNK） cells with primary trophoblasts upregulates the percentage of CD25-expressing pNK cells, resulting in increased expression of activation markers and cytokine production by pNK cells. In addition, we demonstrated that the CXCL12/CXCR4 axis is crucial for the recruitment of CD25^＋ dNK cells and contributes to the accumulation of CD3^-CD56^brightCD25^＋ dNK cells at the maternal/fetal interface. Thus, our data reveal that the crosstalk between trophoblasts and pNK cells leads to the accumulation of CD3^-CD56^brightCD25^＋ dNK cells, which exert a regulating effect at the maternal/fetal interface.
基金This research was supported by the 2020 Joint Research Project of the Institutes of Science and Technology。
文摘In addition to CD4^(+)T cells and neutralizing antibodies,CD8^(+)T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019(COVID-19),an ongoing pandemic disease.In patients with COVID-19,CD8^(+)T cells exhibiting activated phenotypes are commonly observed,although the absolute number of CD8^(+)T cells is decreased.In addition,several studies have reported an upregulation of inhibitory immune checkpoint receptors,such as PD-1,and the expression of exhaustion-associated gene signatures in CD8^(+)T cells from patients with COVID-19.However,whether CD8^(+)T cells are truly exhausted during COVID-19 has been a controversial issue.In the present review,we summarize the current understanding of CD8^(+)T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8^(+)T cells in the context of activation and exhaustion.We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8^(+)T cells and discuss long-term SARS-CoV-2-specific CD8^(+)T-cell memory.
基金supported by start-up funds for Prof. Xin-Yuan Fu (139170082)sponsored by West China Hospital, Sichuan Universityin part by the Chinese National Natural Science Funds (81902947)。
文摘Signal transducers and activators of transcription 5(Stat5)is known to engage in regulating the differentiation and effector function of various subsets of T helper cells.However,how Stat5 regulates the antitumor activity of tumor-infiltrating CD4^(+)T cells is largely unknown.Here,we showed that mice with specific deletion of Stat5 in CD4^(+)T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4^(+)tumor-infiltrating lymphocytes(TILs)remolding.Especially,we confirmed that Stat5-deficient CD4^(+)naïve T cells were prone to polarization of two subtypes of Th17 cells:IFN-γ^(+)and IFN-γ^(-)Th17 cells,which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells.Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma.This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients.
文摘卵巢上皮性癌（卵巢癌）的治疗方法包括手术结合化疗或放疗，但以上方法均未能使晚期卵巢癌患者约30％的5年生存率得以改善，使卵巢癌成为妇科肿瘤中的治疗难点，促使我们寻找新的治疗手段。近年来，免疫治疗成为肿瘤治疗的新辅助方法，显示了一定的治疗效果，其中CD4^＋CD25^＋去调节性T淋巴细胞（regulatory T cells，Tr细胞）成为研究热点，并逐渐从基础研究过渡到临床研究，本文就其在卵巢癌中的研究进展进行综述。
基金supported by the National Natural Science Foundation of China(No.31570931 and No.31771002)the National Key Project for Research&Development of China(Grant no.2016YFA0502204).
文摘Autoreactive CD8^(+)T cells,which play an indispensable role inβcell destruction,represent an emerging target for the prevention of type 1 diabetes(T1D).Altered peptide ligands(APLs)can efficiently induce antigen-specific T cells anergy,apoptosis or shifts in the immune response.Here,we found that HLA-A*0201-restricted CD8^(+)T cell responses against a primaryβ-cell autoantigen insulin epitope InsB15–14 were present in both NOD.β2m null.HHD NOD mice and T1D patients.We generated several APL candidates for InsB15–14 by residue substitution at the p6 position.Only H6F exhibited an inhibitory effect on mInsB1_(5–14)-specific CD8^(+)T cell responses in vitro.H6F treatment significantly reduced the T1D incidence,which was accompanied by diminished autoreactive CD8^(+)T cell responses to mInsB15-14,inhibited infiltration of CD8^(+)and CD4^(+)T cells in the pancreas and reduced pro-inflammatory cytokine production in pancreatic and splenic T cells in NOD.β2m^(null).HHD mice.Mechanistically,H6F treatment significantly augmented a tiny portion of CD8^(+)CD25^(+)Foxp3^(+)T cells in the spleen and especially in the pancreas.This subset exhibited typical Treg phenotypes and required peptide-specific restimulation to exert immunosuppressive activity.Therefore,this APL H6F may be a promising candidate with potential clinical application value for antigen-specific prevention of T1D.
基金National Natural Science Foundation of China(81871784 and 82171822)CAMS Major Collaborative Innovation Project(2016-I2M-1-011,China)+2 种基金Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Project(BZ0150,China)Graduate Innovation Fund(20181007-05,China)Yunnan Science and Technology Talent and Platform Program(202105AG070012,China)。
文摘Berberine(BBR)as one of the most effective natural products has been increasingly used to treat various chronic diseases due to its immunosuppressive/tolerogenic activities.However,it is unknown if BBR can be applied without abrogating the efforts of vaccination.Here we show that priming of CD8^(+)T cells in the presence of BBR lead to improved central memory formation(Tcm)with substantially reduced effector proliferation,primarily orchestrated through activation of AMPK and Stat5.Tcm derived from vaccinated mice fed with BBR were able to adoptively transfer protective immunity to naIve recipients.Vaccination of BBR-fed mice conferred better memory protection against infection without losing immediate effector efficacy,suggesting appreciable benefits from using BBR in vaccination.Thus,our study may help to lay the groundwork for mechanistic understanding of the immunomodulatory effects of natural products and their potential use as adjuvant that allows the design of novel vaccines with more desirable properties.
基金supported by the National Natural Science Foundation of China(81601374)the Fundamental Research Funds for the Central Universities(3332022181)the Bilateral Inter-Governmental S&T Cooperation Project from the Ministry of Science and Technology of China(2018YFE0114300).
文摘Background and Aims:Overexpression of IGF2BP3 is associated with the prognosis of hepatocellular carcinoma(HCC).However,its role in regulating tumor immune microenvironment(TME)is not well characterized.Here,we investigated the effects of IGF2BP3 on macrophages and CD8^(+)T cells within the TME of HCC.Methods:The relationship between IGF2BP3 and immune cell infiltration was analyzed using online bioinformatics tools.Knockout of IGF2BP3 in mouse hepatoma cell line Hepa1-6 was established using CRISPR/Cas9 technology.In vitro cell coculture and subcutaneously implanted hepatoma mice model were used to explore the effects of IGF2BP3 on immune cells.Expression of CCL50l transforming growth factor beta 1(TGF-β1)was detected with quantitative real-time polymerase chain reaction,western blotting,and enzyme-linked immunosorbent assay.The binding of IGF2BP3 and its target RNA was verified by trimolecular fluorescence complementation system and RNA immunoprecipitation followed by quantitative or semiquantitative polymerase chain reaction.Results:IGF2BP3 expression was elevated in HCC and was positively correlated with macrophage infiltration.Patients with higher IGF2BP3 expression and lower macrophage infiltration had a better survival rate.We found that IGF2BP3 could bind to the mRNA of CCL5 or TGF-β1,increasing their expression,and inducing macrophage infiltration and M2 polarization while inhibiting the activation of CD8^(+)T cells.Furthermore,inhibition of IGF2BP3 combined with anti-CD47 antibody treatment significantly suppressed the growth of hepatoma in Hepa1-6 xenograft tu-mor mice.Conclusions:IGF2BP3 promoted the infiltration and M2-polarization of macrophages and suppressed CD8^(+)T activation by enhancing CCL5 and TGF-β1 expression,which facilitated the progression of Hepa1-6 xenograft tumor.
