Objective To investigate the effect of FTY720-treated immature bone marrow-derived dendritic cells（BMDCs） on the embryo resorption rate in the CBA/J× DBA/2 abortion mouse model.Methods The dendritic cells（DCs...Objective To investigate the effect of FTY720-treated immature bone marrow-derived dendritic cells（BMDCs） on the embryo resorption rate in the CBA/J× DBA/2 abortion mouse model.Methods The dendritic cells（DCs） were derived from bone marrow of DBA/2 mice, and then co-cultured with FTY720. The abortion mouse models were established by mating female CBA/J mice with DBA/2 mice. Via the CBA/J×DBA/2 abortion mouse model, six groups were established, group A： normal pregnancy model; group B： abortion mouse model with no treatment; group C： abortion mouse model injected with DC culture medium（DCCM）; group D： abortion mouse model injected with DC; group E： abortion mouse model injected with FTY720; group F： abortion model mouse injected with FTY720-DC. The differences were compared in the embryo resorption rates of the CBA/J ×DBA/2 abortion mouse model treated with FTY720-DC or different controls observed on gestation day 12 to 14, and then the microenvironment in murine pregnancy was investigated.Results The embryo resorption rate was statistically significantly decreased in group D and group E when they compared with group B and group C（P〈0.05, respectively）.Furthermore, the embryo resorption rate in group F showed a statistically significant decrease when compared with the other groups except group A（P〈0.01）. These resultssuggest that FTY720-DCs possess a notable advantage over DCs or FTY720 in reducing the embryo resorption rate of the abortion mouse model. The percentage of Th17（IL-17＋CD4＋T cells） in peripheral blood mononuclear cell（PBMC） in the abortion mouse model was 4.35%±0.34% before treated with FTY720-DC, and was1.34%±0.28% after treated with FTY720-DC（P〈0.01）. The percentage of Tregs（CD4~＋CD25~＋Foxp3~＋T cells） in PBMC was significantly increased in group F（8.35%±1.80%） as compared with group B（2.68%±0.65%）（P〈0.01）.Conclusion Adoptive transfer of FTY720-DC can statistically significantly reduce the embryo resorption rate in the CBA/J×DBA/2 abortion mouse model. The lower embryo resorption rate in the FTY720-DC treated abortion mouse model may be caused by the imbalance of Treg/Th17.展开更多
Objective To generate a chronic lymphocytic leukemia(CLL) mouse model with intact immune competence and short latency by adoptively transferring(AT) splenocytes from immunoglobulin heavy-chain enhancer-driven T-cell l...Objective To generate a chronic lymphocytic leukemia(CLL) mouse model with intact immune competence and short latency by adoptively transferring(AT) splenocytes from immunoglobulin heavy-chain enhancer-driven T-cell leukemia/lymphoma 1 (Eμ-TCLl) transgenic donors into wild-type(WT) recipients.展开更多
Atherosclerosis is characterized by inflammation in the arterial wall,which is known to be exacerbated by diabetes.Therapeutic repression of inflammation is a promising strategy for treating atherosclerosis.In this st...Atherosclerosis is characterized by inflammation in the arterial wall,which is known to be exacerbated by diabetes.Therapeutic repression of inflammation is a promising strategy for treating atherosclerosis.In this study,we showed that diabetes aggravated atherosclerosis in apolipoproteinE knockout(ApoE^(-/-))mice,in which increased expression of long-chain acyl-CoA synthetase 1(Acsl1)in macrophages played an important role.Knockdown of Acsl1 in macrophages(Mφ^(shAcsl1))reprogrammed macrophages to an anti-inflammatory phenotype,especially under hyperglycemic conditions.Injection of Mφ^(shAcsl1) reprogrammed macrophages into streptozotocin(STZ)-induced diabetic ApoE^(-/-) mice(ApoE^(-/-)+STZ)alleviated inflammation locally in the plaque,liver and spleen.Consistent with the reduction in inflammation,plaques became smaller and more stable after the adoptive transfer of reprogrammed macrophages.Taken together,our findings indicate that increased Acsl1 expression in macrophages play a key role in aggravated atherosclerosis of diabetic mice,possibly by promoting inflammation.Adoptive transfer of Acsl1 silenced macrophages may serve as a potential therapeutic strategy for atherosclerosis.展开更多
Background Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease （GVHD）. Here, we sought to maximize graft-versus-tumor and minimize GVHD by using haploidentical T ...Background Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease （GVHD）. Here, we sought to maximize graft-versus-tumor and minimize GVHD by using haploidentical T cells in pre-irradiated B16-melanoma bearing mice.展开更多
AIM: To assess the anti-inflammatory effect of the probiotic Bifidobacterium lactis (B. lactis) in an adoptive transfer model of colitis. METHODS: Donor and recipient mice received either B. lactis or bacterial cultur...AIM: To assess the anti-inflammatory effect of the probiotic Bifidobacterium lactis (B. lactis) in an adoptive transfer model of colitis. METHODS: Donor and recipient mice received either B. lactis or bacterial culture medium as control (deMan Rogosa Sharpe) in drinking water for one week prior to transfer of a mix of naive and regulatory T cells until sacrifice. RESULTS: All recipient mice developed signs of colonic inflammation, but a significant reduction of weight loss was observed in B. lactis-fed recipient mice compared to control mice. Moreover, a trend toward a diminution of mucosal thickness and attenuated epithelial damage was revealed. Colonic expression of pro-inflammatory and T cell markers was significantly reduced in B. lactis-fed recipient mice compared to controls. Concomitantly, forkhead box protein 3, a marker of regulatory T cells, was significantly up-regulated by B. lactis. CONCLUSION: Daily oral administration of B. lactis was able to reduce inflammatory and T cells mediators and to promote regulatory T cells specific markers in a mouse model of colitis.展开更多
Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have pre...Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Thl responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4＋CD25＋ T cells from the immunized mice. Moreover, CD4＋CD25＋Foxp3＋ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naive mice. Further analysis showed that the serum of immunized mice contains a high level ofanti-CD25 antibody （about 30 ng/ml, p〈0.01 vs controls）. Consistent with a role ofanti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naive mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4＋CD25＋Foxp3＋ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Thl response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.展开更多
Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory diseases.These models help elucidatethe mechanisms underlying the disease and in the developmen...Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory diseases.These models help elucidatethe mechanisms underlying the disease and in the development of novel therapies.However,if mice are deficient in certain cells and/or effectors associated with human diseases,how can their functions be investigated in this species?Mucosal-associated invariant T(MAIT)cells,a novel innate-like T cell family member,are a good example.MAIT cells are abundant in humans but scarce in laboratory mice.MAIT cells harbor an invariant T cell receptor and recognize nonpeptidic antigens vitamin B2metabolites from bacteria and yeasts.Recent studies have shown that MAIT cells play a pivotal role in human diseases such as bacterial infections and autoimmune and inflammatory diseases.MAIT cells possess granulysin,a human-specific effector molecule,but granulysin and its homologue are absent in mice.Furthermore,MAIT cells show poor proliferation in vitro.To overcome these problems and further our knowledge of MAIT cells,we have established a method to expand MAIT cells via induced pluripotent stem cells(iP SCs).In this review,we describe recent advances in the field of MAIT cell research and our approach for human disease modeling with iP SCderived MAIT cells.展开更多
Objective To investigate the role of T cell and its subsets in the induction of insulifis and type 1 diabetes mellitus （T1DM） in BALB/c mice. Methods Autoimmune diabetes mellitus was developed by intraperitoneal in...Objective To investigate the role of T cell and its subsets in the induction of insulifis and type 1 diabetes mellitus （T1DM） in BALB/c mice. Methods Autoimmune diabetes mellitus was developed by intraperitoneal injection of 40 mg/kg streptozotocin （STZ） daily for 5 consecutive days in BALB/c mice as sources of donor cells. Spleen cells from diabetic mice were then cultured for 7 days in the stimulation of interleukin-2 （IL-2） to harvest diabetogenic T cells, which were subse-quently transferred into normal BALB/c mice recipients. MTT, ELISA, and HE staining were used to analyze the lym- phocyte proliferation, cytokine （ IL-2, interferon-γ, IL-4, and IL-10） levels, and pathological changes in pancreatic is- lets. Results As few as 3×10^6 diabetogenic T cells successfully induced diabetes mellitus in recipients pretreated with STZ twice, whereas transfer of equal amount of normal splenocytes, T cell-depleted diabetogenic splenocytes, or diabe-togenic CD4^＋ T cells alone in recipients receiving STZ twice pretreatment was proved not to induce diabetes mellitus either. A markedly increased lymphocyte proliferation, high levels of interferon-γ/and IL-2 in the supernatants of diabeto-genic T cells were observed. In addition, a markedly enhanced lymphocyte proliferation, a high level of interferon-γ/secretion in serum, and numerous lymphocytes infiltration in pancreatic islets were detected in the diabetic mice induced by diabetogenic T cells transfer. Conclusions A novel T1DM murine model is established in STZ-pretreated BALB/c mice by adoptive transfer of diabetogenic T cells. CD4^＋ T cells with interferon-γ/may promote the onset of diabetes mellitus.展开更多
Liver transplantation(LT)has emerged as a curative strategy for hepatocellular carcinoma(HCC),but contributes to a higher predisposition to HCC recurrence in the immunosuppression context,especially for tumors beyond ...Liver transplantation(LT)has emerged as a curative strategy for hepatocellular carcinoma(HCC),but contributes to a higher predisposition to HCC recurrence in the immunosuppression context,especially for tumors beyond the Milan criteria.Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors,including HCC,it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection.Nevertheless,accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC,from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting.Generally,immunotherapy mainly includes immune checkpoint inhibitors(ICIs),adoptive cell transfer(ACT)and vaccine therapy.ICIs,followed by ACT,have been most investigated in LT,with some promising results.Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy,it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients.In addition,the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT.In this review,we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC.Moreover,we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.展开更多
BACKGROUND:Recurrence of hepatitis B virus(HBV) infection after liver transplantation can lead to graft loss and a reduction in long-term survival.The purpose of this review is to summarize the current therapeutic opt...BACKGROUND:Recurrence of hepatitis B virus(HBV) infection after liver transplantation can lead to graft loss and a reduction in long-term survival.The purpose of this review is to summarize the current therapeutic options for preventing HBV recurrence in liver transplant recipients.DATA SOURCES:Up to January 2013,studies that were published in MEDLINE and EMBASE on prevention of HBV recurrence after liver transplantation were reviewed.RESULTS:There have been remarkable advancements in the past two decades on the prevention of HBV recurrence after liver transplantation,from the discovery of hepatitis B immune globulin(HBIG) and lamivudine monotherapy to the combination therapy using HBIG and lamivudine.With the development of newer and stronger antiviral agents,the need for life-long HBIG is doubtful.With their low resistance profile,oral antiviral prophylaxis using these new agents alone is sufficient and is associated with excellent outcome.CONCLUSIONS:Restoration of host HBV immunity with adoptive immunity transfer and vaccination may represent the ultimate strategy to withdraw prophylactic treatment and to achieve a drug free regimen against HBV recurrence after liver transplantation.展开更多
Natural killer(NK)cells represent a promising future for tumor immunotherapy because of their unique biological functions and characteristics.This review focuses on technical advances in NK cell-based cellular immunot...Natural killer(NK)cells represent a promising future for tumor immunotherapy because of their unique biological functions and characteristics.This review focuses on technical advances in NK cell-based cellular immunotherapy and summarizes the developments of recent years in cell sources,genetic modification,manufacturing systems,clinical programs,and outcomes.Future prospects and challenges in NK cell immunotherapy are also discussed,including off-the-shelf NK cell exploitation,automatic and closed manufacturing systems,cryopreservation,and therapies involving regulatory checkpoints.展开更多
The environment surrounding a tumor,known as the tumor microenvironment(TME),plays a role in how cancer progresses and responds to treatment.It poses both challenges and opportunities for improving cancer therapy.Rece...The environment surrounding a tumor,known as the tumor microenvironment(TME),plays a role in how cancer progresses and responds to treatment.It poses both challenges and opportunities for improving cancer therapy.Recent progress in understanding the TME complexity and diversity has led to approaches for treating cancer.This perspective discusses the strategies for targeting the TME,such as adjusting networks using extracellular vesicles to deliver drugs and enhancing immune checkpoint inhibitors(ICIS)through combined treatments.Furthermore,it highlights adoptive cell transfer(ACT)therapies as an option for tumors.By studying how components of the TME interact and utilizing technologies like single-cell RNA sequencing and spatial transcriptomics,we can develop more precise and efficient treatments for cancer.This article emphasizes the need to reshape the TME to boost antitumor immunity and overcome resistance to therapy,providing guidance for research and clinical practices in precision oncology.展开更多
Natural killer(NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex(MHC) matching, play pivotal roles in immune defence against tumors. However, tumo...Natural killer(NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex(MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor(CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell-based approaches may hold great potential for future cancer immunotherapy.展开更多
Natural killer cells （NKs） have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including...Natural killer cells （NKs） have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells （PBMCs）, stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.展开更多
The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induce...The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConA- mediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell （Treg）- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.展开更多
Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases(CVDs).Regulatory T cells(Tregs)are typical immune regulatory cells with recognized immunosuppressive properties.Despi...Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases(CVDs).Regulatory T cells(Tregs)are typical immune regulatory cells with recognized immunosuppressive properties.Despite the immunosuppressive properties,researchers have acknowledged the significance of Tregs in maintaining tissue homeostasis and facilitating repair/regeneration.Previous studies unveiled the heterogeneity of Tregs in the heart and aorta,which expanded in CVDs with unique transcriptional phenotypes and reparative/regenerative function.This review briefly summarizes the functional principles of Tregs,also including the synergistic effect of Tregs and other immune cells in CVDs.We discriminate the roles and therapeutic potential of Tregs in CVDs such as atherosclerosis,hypertension,abdominal arterial aneurysm,pulmonary arterial hypertension,Kawasaki disease,myocarditis,myocardial infarction,and heart failure.Tregs not only exert anti-inflammatory effects but also actively promote myocardial regeneration and vascular repair,maintaining the stability of the local microenvironment.Given that the specific mechanism of Tregs functioning in CVDs remains unclear,we reviewed previous clinical and basic studies and the latest findings on the function and mechanism of Tregs in CVDs.展开更多
Background Adoptive cell transfer （ACT） immunotherapy has been used clinically for years to treat malignancies.Improving the killing efficiency of effector cells,such as tumor-specific cytotoxic T lymphocytes （CTLs...Background Adoptive cell transfer （ACT） immunotherapy has been used clinically for years to treat malignancies.Improving the killing efficiency of effector cells,such as tumor-specific cytotoxic T lymphocytes （CTLs）,is an important component for enhancing the clinical response of cancer immunotherapy.Hence,we explored a novel method for preparing cancer-specific CTLs using naive T lymphocytes.Methods C57BL/6 mice bearing B16 melanoma tumors were pretreated with cyclophosphamide （CTX） by peritoneal injection.The immunosuppressive influence of CTX on tumor regression and the tumor microenvironment was assessed.Naive T cells and T cell pools were isolated via negative selection using immunomagnetic beads.The proliferative potential and cytokine production of different T cell subpopulations were evaluated in vitro.Tumor-specific CTLs derived from naive T cells （naive CD4＋ T cells：naive CD8＋ T cells=2：1） and pooled T cells were generated in vitro,respectively.B16 melanoma-bearing C57BL/6 mice were pretreated with CTX,followed by ACT immunotherapy using dendritic cell-induced CTLs.The homing abilities of the effector cells and interleukin-2 （IL-2）,interferon-y,granzyme B,and perforin mRNA levels in tumor tissues were evaluated,and the change in tumor volume was measured.Results Mice receiving CTX peritoneal pretreatment injections did not display tumor regression compared with control mice.However,a significant downregulation of splenic Tregs and tumor growth factor-β1 （TGF-β1） and interleukin-10 （IL-10） serum levels was observed （P ＜0.05）.Naive T cells showed a stronger proliferative capacity and elevated cytokine production than did pooled T cells （P ＜0.05）.In addition,effector cells generated from naive T cells displayed more potent antitumor activity in vivo than those derived from pooled T cells （P ＜0.05）.Conclusion Effector cells derived from the naive T cells possess a stronger proliferative potential,homing capacity,and enhanced cytokine production,which leads to a superior antitumor response.展开更多
The initiation and development of major infammatory diseases,i.e.,cancer,vascular infammation,and some autoimmune diseases are closely linked to the immune system.Biologics-based immunotherapy is exerting a critical r...The initiation and development of major infammatory diseases,i.e.,cancer,vascular infammation,and some autoimmune diseases are closely linked to the immune system.Biologics-based immunotherapy is exerting a critical role against these diseases,whereas the usage of the immunomodulators is always limited by various factors such as susceptibility to digestion by enzymes in vivo,poor penetration across biological barriers,and rapid clearance by the reticuloendothelial system.Drug delivery strategies are potent to promote their delivery.Herein,we reviewed the potential targets for immunotherapy against the major infammatory diseases,discussed the biologics and drug delivery systems involved in the immunotherapy,particularly highlighted the approved therapy tactics,and finally offer perspectives in this feld.展开更多
Cancer immunotherapy has become a new generation of anti-tumor treatment,but its indications still focus on several types of tumors that are sensitive to the immune system.Therefore,effective strategies that can expan...Cancer immunotherapy has become a new generation of anti-tumor treatment,but its indications still focus on several types of tumors that are sensitive to the immune system.Therefore,effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy.Natural products are reported to have this effect on cancer immunotherapy,including cancer vaccines,immune-check points inhibitors,and adoptive immune-cells therapy.And the mechanism of that is mainly attributed to the remodeling of the tumorimmunosuppressive microenvironment,which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy.Therefore,this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism.And we found that saponins,polysaccharides,and flavonoids are mainly three categories of natural products,which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment.Besides,this review also collected the studies about nano-technology used to improve the disadvantages of natural products.All of these studies showed the great potential of natural products in cancer immunotherapy.展开更多
γδT cells are of interest as effector cells for cellular immunotherapy due to their HLA-non-restricted lysis of many different tumor cell types.Potential applications include the adoptive transfer of in vitro-expan...γδT cells are of interest as effector cells for cellular immunotherapy due to their HLA-non-restricted lysis of many different tumor cell types.Potential applications include the adoptive transfer of in vitro-expandedγδT cells.Therefore,it is important to optimize the culture conditions to enable maximal proliferative and functional activity.Vitamin C(L-ascorbic acid)is an essential vitamin with multiple effects on immune cells.It is a cofactor for several enzymes,has antioxidant activity,and is an epigenetic modifier.Here,we investigated the effects of vitamin C(VC)and its more stable derivative,L-ascorbic acid 2-phosphate(pVC),on the proliferation and effector function of humanγδT cells stimulated with zoledronate(ZOL)or synthetic phosphoantigens(pAgs).VC and pVC did not increaseγδT-cell expansion within ZOL-or pAg-stimulated PBMCs,but increased the proliferation of purifiedγδT cells and 14-day-expandedγδT-cell lines in response toγδT-cell-specific pAgs.VC reduced the apoptosis ofγδT cells during primary stimulation.While pVC did not prevent activation-induced death of pAg-restimulatedγδT cells,it enhanced the cell cycle progression and cellular expansion.Furthermore,VC and pVC enhanced cytokine production during primary activation,as well as upon pAg restimulation of 14-day-expandedγδT cells.VC and pVC also increased the oxidative respiration and glycolysis ofγδT cells,but stimulus-dependent differences were observed.The modulatory activity of VC and pVC might help to increase the efficacy ofγδT-cell expansion for adoptive immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.81200477)
文摘Objective To investigate the effect of FTY720-treated immature bone marrow-derived dendritic cells（BMDCs） on the embryo resorption rate in the CBA/J× DBA/2 abortion mouse model.Methods The dendritic cells（DCs） were derived from bone marrow of DBA/2 mice, and then co-cultured with FTY720. The abortion mouse models were established by mating female CBA/J mice with DBA/2 mice. Via the CBA/J×DBA/2 abortion mouse model, six groups were established, group A： normal pregnancy model; group B： abortion mouse model with no treatment; group C： abortion mouse model injected with DC culture medium（DCCM）; group D： abortion mouse model injected with DC; group E： abortion mouse model injected with FTY720; group F： abortion model mouse injected with FTY720-DC. The differences were compared in the embryo resorption rates of the CBA/J ×DBA/2 abortion mouse model treated with FTY720-DC or different controls observed on gestation day 12 to 14, and then the microenvironment in murine pregnancy was investigated.Results The embryo resorption rate was statistically significantly decreased in group D and group E when they compared with group B and group C（P〈0.05, respectively）.Furthermore, the embryo resorption rate in group F showed a statistically significant decrease when compared with the other groups except group A（P〈0.01）. These resultssuggest that FTY720-DCs possess a notable advantage over DCs or FTY720 in reducing the embryo resorption rate of the abortion mouse model. The percentage of Th17（IL-17＋CD4＋T cells） in peripheral blood mononuclear cell（PBMC） in the abortion mouse model was 4.35%±0.34% before treated with FTY720-DC, and was1.34%±0.28% after treated with FTY720-DC（P〈0.01）. The percentage of Tregs（CD4~＋CD25~＋Foxp3~＋T cells） in PBMC was significantly increased in group F（8.35%±1.80%） as compared with group B（2.68%±0.65%）（P〈0.01）.Conclusion Adoptive transfer of FTY720-DC can statistically significantly reduce the embryo resorption rate in the CBA/J×DBA/2 abortion mouse model. The lower embryo resorption rate in the FTY720-DC treated abortion mouse model may be caused by the imbalance of Treg/Th17.
文摘Objective To generate a chronic lymphocytic leukemia(CLL) mouse model with intact immune competence and short latency by adoptively transferring(AT) splenocytes from immunoglobulin heavy-chain enhancer-driven T-cell leukemia/lymphoma 1 (Eμ-TCLl) transgenic donors into wild-type(WT) recipients.
基金funded by the National Natural Science Foundation of China(No,81671910 to X Yang)Shanxi Province Foundation of China(No.2021SF-341 to X Yang).
文摘Atherosclerosis is characterized by inflammation in the arterial wall,which is known to be exacerbated by diabetes.Therapeutic repression of inflammation is a promising strategy for treating atherosclerosis.In this study,we showed that diabetes aggravated atherosclerosis in apolipoproteinE knockout(ApoE^(-/-))mice,in which increased expression of long-chain acyl-CoA synthetase 1(Acsl1)in macrophages played an important role.Knockdown of Acsl1 in macrophages(Mφ^(shAcsl1))reprogrammed macrophages to an anti-inflammatory phenotype,especially under hyperglycemic conditions.Injection of Mφ^(shAcsl1) reprogrammed macrophages into streptozotocin(STZ)-induced diabetic ApoE^(-/-) mice(ApoE^(-/-)+STZ)alleviated inflammation locally in the plaque,liver and spleen.Consistent with the reduction in inflammation,plaques became smaller and more stable after the adoptive transfer of reprogrammed macrophages.Taken together,our findings indicate that increased Acsl1 expression in macrophages play a key role in aggravated atherosclerosis of diabetic mice,possibly by promoting inflammation.Adoptive transfer of Acsl1 silenced macrophages may serve as a potential therapeutic strategy for atherosclerosis.
文摘Background Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease （GVHD）. Here, we sought to maximize graft-versus-tumor and minimize GVHD by using haploidentical T cells in pre-irradiated B16-melanoma bearing mice.
文摘AIM: To assess the anti-inflammatory effect of the probiotic Bifidobacterium lactis (B. lactis) in an adoptive transfer model of colitis. METHODS: Donor and recipient mice received either B. lactis or bacterial culture medium as control (deMan Rogosa Sharpe) in drinking water for one week prior to transfer of a mix of naive and regulatory T cells until sacrifice. RESULTS: All recipient mice developed signs of colonic inflammation, but a significant reduction of weight loss was observed in B. lactis-fed recipient mice compared to control mice. Moreover, a trend toward a diminution of mucosal thickness and attenuated epithelial damage was revealed. Colonic expression of pro-inflammatory and T cell markers was significantly reduced in B. lactis-fed recipient mice compared to controls. Concomitantly, forkhead box protein 3, a marker of regulatory T cells, was significantly up-regulated by B. lactis. CONCLUSION: Daily oral administration of B. lactis was able to reduce inflammatory and T cells mediators and to promote regulatory T cells specific markers in a mouse model of colitis.
基金This work was supported by National Natural Science Foundation of China(No.30671945)Science and Technology Commission of Shanghai Municipality(Nos.06JC14044,05ZR14055,054319928,04DZ14902)+2 种基金Shanghai Municipal Education(No.05BZ26)Shanghai Leading Academic Discipline Project(T0206)Science Foundation of Shanghai Institute of Immunology(No.07-A04,to Ningli Li).
文摘Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Thl responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4＋CD25＋ T cells from the immunized mice. Moreover, CD4＋CD25＋Foxp3＋ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naive mice. Further analysis showed that the serum of immunized mice contains a high level ofanti-CD25 antibody （about 30 ng/ml, p〈0.01 vs controls）. Consistent with a role ofanti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naive mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4＋CD25＋Foxp3＋ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Thl response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.
文摘Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory diseases.These models help elucidatethe mechanisms underlying the disease and in the development of novel therapies.However,if mice are deficient in certain cells and/or effectors associated with human diseases,how can their functions be investigated in this species?Mucosal-associated invariant T(MAIT)cells,a novel innate-like T cell family member,are a good example.MAIT cells are abundant in humans but scarce in laboratory mice.MAIT cells harbor an invariant T cell receptor and recognize nonpeptidic antigens vitamin B2metabolites from bacteria and yeasts.Recent studies have shown that MAIT cells play a pivotal role in human diseases such as bacterial infections and autoimmune and inflammatory diseases.MAIT cells possess granulysin,a human-specific effector molecule,but granulysin and its homologue are absent in mice.Furthermore,MAIT cells show poor proliferation in vitro.To overcome these problems and further our knowledge of MAIT cells,we have established a method to expand MAIT cells via induced pluripotent stem cells(iP SCs).In this review,we describe recent advances in the field of MAIT cell research and our approach for human disease modeling with iP SCderived MAIT cells.
基金Supported by the National Natural Science Foundation of China(30200343)
文摘Objective To investigate the role of T cell and its subsets in the induction of insulifis and type 1 diabetes mellitus （T1DM） in BALB/c mice. Methods Autoimmune diabetes mellitus was developed by intraperitoneal injection of 40 mg/kg streptozotocin （STZ） daily for 5 consecutive days in BALB/c mice as sources of donor cells. Spleen cells from diabetic mice were then cultured for 7 days in the stimulation of interleukin-2 （IL-2） to harvest diabetogenic T cells, which were subse-quently transferred into normal BALB/c mice recipients. MTT, ELISA, and HE staining were used to analyze the lym- phocyte proliferation, cytokine （ IL-2, interferon-γ, IL-4, and IL-10） levels, and pathological changes in pancreatic is- lets. Results As few as 3×10^6 diabetogenic T cells successfully induced diabetes mellitus in recipients pretreated with STZ twice, whereas transfer of equal amount of normal splenocytes, T cell-depleted diabetogenic splenocytes, or diabe-togenic CD4^＋ T cells alone in recipients receiving STZ twice pretreatment was proved not to induce diabetes mellitus either. A markedly increased lymphocyte proliferation, high levels of interferon-γ/and IL-2 in the supernatants of diabeto-genic T cells were observed. In addition, a markedly enhanced lymphocyte proliferation, a high level of interferon-γ/secretion in serum, and numerous lymphocytes infiltration in pancreatic islets were detected in the diabetic mice induced by diabetogenic T cells transfer. Conclusions A novel T1DM murine model is established in STZ-pretreated BALB/c mice by adoptive transfer of diabetogenic T cells. CD4^＋ T cells with interferon-γ/may promote the onset of diabetes mellitus.
基金National Natural Science Foundation of China,No.81702923 and No.81871262.
文摘Liver transplantation(LT)has emerged as a curative strategy for hepatocellular carcinoma(HCC),but contributes to a higher predisposition to HCC recurrence in the immunosuppression context,especially for tumors beyond the Milan criteria.Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors,including HCC,it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection.Nevertheless,accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC,from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting.Generally,immunotherapy mainly includes immune checkpoint inhibitors(ICIs),adoptive cell transfer(ACT)and vaccine therapy.ICIs,followed by ACT,have been most investigated in LT,with some promising results.Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy,it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients.In addition,the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT.In this review,we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC.Moreover,we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.
文摘BACKGROUND:Recurrence of hepatitis B virus(HBV) infection after liver transplantation can lead to graft loss and a reduction in long-term survival.The purpose of this review is to summarize the current therapeutic options for preventing HBV recurrence in liver transplant recipients.DATA SOURCES:Up to January 2013,studies that were published in MEDLINE and EMBASE on prevention of HBV recurrence after liver transplantation were reviewed.RESULTS:There have been remarkable advancements in the past two decades on the prevention of HBV recurrence after liver transplantation,from the discovery of hepatitis B immune globulin(HBIG) and lamivudine monotherapy to the combination therapy using HBIG and lamivudine.With the development of newer and stronger antiviral agents,the need for life-long HBIG is doubtful.With their low resistance profile,oral antiviral prophylaxis using these new agents alone is sufficient and is associated with excellent outcome.CONCLUSIONS:Restoration of host HBV immunity with adoptive immunity transfer and vaccination may represent the ultimate strategy to withdraw prophylactic treatment and to achieve a drug free regimen against HBV recurrence after liver transplantation.
基金supported by grants from the Chinese Academy of Sciences (Grant No. XDB29030201, XBD29030202)the Ministry of Science and Technology of China (Grant No. 2016YFC1303503)+2 种基金the National Natural Science Foundation of China (Grant No. 81788101, 81671558, 31571440, 81821001, 91542000)Major Projects of Science and Technology in Anhui Province (Grant No. 17030801024)the Fundamental Research Funds for the Central Universities (Grant No. YD2070002004)
文摘Natural killer(NK)cells represent a promising future for tumor immunotherapy because of their unique biological functions and characteristics.This review focuses on technical advances in NK cell-based cellular immunotherapy and summarizes the developments of recent years in cell sources,genetic modification,manufacturing systems,clinical programs,and outcomes.Future prospects and challenges in NK cell immunotherapy are also discussed,including off-the-shelf NK cell exploitation,automatic and closed manufacturing systems,cryopreservation,and therapies involving regulatory checkpoints.
基金supported by a grant from the Public Welfare Projects of Ningbo,China(2020S065)the Health Major Science and Technology Planning Project of Zhejiang,China(WKJ-ZJ-2411),and a grant from the Project of Ningbo Leading Medical&Health Discipline(2022-F23).
文摘The environment surrounding a tumor,known as the tumor microenvironment(TME),plays a role in how cancer progresses and responds to treatment.It poses both challenges and opportunities for improving cancer therapy.Recent progress in understanding the TME complexity and diversity has led to approaches for treating cancer.This perspective discusses the strategies for targeting the TME,such as adjusting networks using extracellular vesicles to deliver drugs and enhancing immune checkpoint inhibitors(ICIS)through combined treatments.Furthermore,it highlights adoptive cell transfer(ACT)therapies as an option for tumors.By studying how components of the TME interact and utilizing technologies like single-cell RNA sequencing and spatial transcriptomics,we can develop more precise and efficient treatments for cancer.This article emphasizes the need to reshape the TME to boost antitumor immunity and overcome resistance to therapy,providing guidance for research and clinical practices in precision oncology.
基金supported by grants from the Ministry of Science and Technology of China(2014CB910104)the National Natural Science Foundation of China(81171899+1 种基金81372230)the Claudia Adams Barr Program for Innovative Cancer Research
文摘Natural killer(NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex(MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor(CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell-based approaches may hold great potential for future cancer immunotherapy.
基金This work was supported by the National Natural Science Foundation of China （Nos. 81788101, 91542000, 81671558, and 31571440） the Ministry of Science and Technology of China （No. 2016YFC1303503） and Chinese Academy of Sciences （Nos. XDA12020312, XDPB030301, and XDPB030303）.
文摘Natural killer cells （NKs） have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells （PBMCs）, stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.
基金ACKNOWLEDGEMENTS This work was supported by grants from the National Basic Research Program （973 Program） （Nos. 2012CB517603 and 2011CB504803）, the National Natural Science Foundation of China （Grant No. 31301061）, the Natural Science Foundation of Jiangsu Province （No. BK2011013 and BK20130564）, and the Specialized Research Fund for the Doctoral Program of Higher Education （20130091120037）.
文摘The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConA- mediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell （Treg）- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.
基金National Natural Science Foundation of China(Nos.82030016 and 82230011 to Xiang Cheng and No.82000443 to Jingyong Li)
文摘Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases(CVDs).Regulatory T cells(Tregs)are typical immune regulatory cells with recognized immunosuppressive properties.Despite the immunosuppressive properties,researchers have acknowledged the significance of Tregs in maintaining tissue homeostasis and facilitating repair/regeneration.Previous studies unveiled the heterogeneity of Tregs in the heart and aorta,which expanded in CVDs with unique transcriptional phenotypes and reparative/regenerative function.This review briefly summarizes the functional principles of Tregs,also including the synergistic effect of Tregs and other immune cells in CVDs.We discriminate the roles and therapeutic potential of Tregs in CVDs such as atherosclerosis,hypertension,abdominal arterial aneurysm,pulmonary arterial hypertension,Kawasaki disease,myocarditis,myocardial infarction,and heart failure.Tregs not only exert anti-inflammatory effects but also actively promote myocardial regeneration and vascular repair,maintaining the stability of the local microenvironment.Given that the specific mechanism of Tregs functioning in CVDs remains unclear,we reviewed previous clinical and basic studies and the latest findings on the function and mechanism of Tregs in CVDs.
文摘Background Adoptive cell transfer （ACT） immunotherapy has been used clinically for years to treat malignancies.Improving the killing efficiency of effector cells,such as tumor-specific cytotoxic T lymphocytes （CTLs）,is an important component for enhancing the clinical response of cancer immunotherapy.Hence,we explored a novel method for preparing cancer-specific CTLs using naive T lymphocytes.Methods C57BL/6 mice bearing B16 melanoma tumors were pretreated with cyclophosphamide （CTX） by peritoneal injection.The immunosuppressive influence of CTX on tumor regression and the tumor microenvironment was assessed.Naive T cells and T cell pools were isolated via negative selection using immunomagnetic beads.The proliferative potential and cytokine production of different T cell subpopulations were evaluated in vitro.Tumor-specific CTLs derived from naive T cells （naive CD4＋ T cells：naive CD8＋ T cells=2：1） and pooled T cells were generated in vitro,respectively.B16 melanoma-bearing C57BL/6 mice were pretreated with CTX,followed by ACT immunotherapy using dendritic cell-induced CTLs.The homing abilities of the effector cells and interleukin-2 （IL-2）,interferon-y,granzyme B,and perforin mRNA levels in tumor tissues were evaluated,and the change in tumor volume was measured.Results Mice receiving CTX peritoneal pretreatment injections did not display tumor regression compared with control mice.However,a significant downregulation of splenic Tregs and tumor growth factor-β1 （TGF-β1） and interleukin-10 （IL-10） serum levels was observed （P ＜0.05）.Naive T cells showed a stronger proliferative capacity and elevated cytokine production than did pooled T cells （P ＜0.05）.In addition,effector cells generated from naive T cells displayed more potent antitumor activity in vivo than those derived from pooled T cells （P ＜0.05）.Conclusion Effector cells derived from the naive T cells possess a stronger proliferative potential,homing capacity,and enhanced cytokine production,which leads to a superior antitumor response.
基金supported by the National Natural Science Foundation of China(Nos.81872823 and 82073782)the Double FirstClass(CPU2018PZQ13,China)of the China Pharmaceutical University,the Shanghai Science and Technology Committee(No.19430741500,China)+1 种基金the Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education of Jiangxi University of Traditional Chinese Medicine(TCM-201905,China)the Start-up Grant from City University of Hong Kong(No.9610472,China)。
文摘The initiation and development of major infammatory diseases,i.e.,cancer,vascular infammation,and some autoimmune diseases are closely linked to the immune system.Biologics-based immunotherapy is exerting a critical role against these diseases,whereas the usage of the immunomodulators is always limited by various factors such as susceptibility to digestion by enzymes in vivo,poor penetration across biological barriers,and rapid clearance by the reticuloendothelial system.Drug delivery strategies are potent to promote their delivery.Herein,we reviewed the potential targets for immunotherapy against the major infammatory diseases,discussed the biologics and drug delivery systems involved in the immunotherapy,particularly highlighted the approved therapy tactics,and finally offer perspectives in this feld.
基金supported by Science and Technology Plan Project of Shenyang(RC200406,China)the Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University(Shenyang,China)。
文摘Cancer immunotherapy has become a new generation of anti-tumor treatment,but its indications still focus on several types of tumors that are sensitive to the immune system.Therefore,effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy.Natural products are reported to have this effect on cancer immunotherapy,including cancer vaccines,immune-check points inhibitors,and adoptive immune-cells therapy.And the mechanism of that is mainly attributed to the remodeling of the tumorimmunosuppressive microenvironment,which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy.Therefore,this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism.And we found that saponins,polysaccharides,and flavonoids are mainly three categories of natural products,which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment.Besides,this review also collected the studies about nano-technology used to improve the disadvantages of natural products.All of these studies showed the great potential of natural products in cancer immunotherapy.
基金This work was supported by grant Ka 502/19-1 fromthe German Research Council(Deutsche Forschungsgemeinschaft)to D.K.the Cluster of Excellence ExC 306"Inflammation-at-Interfaces"(Deutsche Forschungs-gemeinschaft)to D.K+6 种基金L.K.was supported by a long-term fellowship from the German Academic Exchange Service(DAAD)C.P.is the recipient of a grant fromthe Erich und Gertrud Roggenbruck FoundationThis work was also supported by the Major International Joint Research Program of China(Grant 31420103901)the Key Program of the National Natural Science Foundation of China(Grant31830021)the"111"project(816021)the Incubating Program from the Science and Technology Department of Guangdong Province of China(Grant2014A030308003)Guangzhou Science and Technology Key Project(201604020006)to Z.Y.
文摘γδT cells are of interest as effector cells for cellular immunotherapy due to their HLA-non-restricted lysis of many different tumor cell types.Potential applications include the adoptive transfer of in vitro-expandedγδT cells.Therefore,it is important to optimize the culture conditions to enable maximal proliferative and functional activity.Vitamin C(L-ascorbic acid)is an essential vitamin with multiple effects on immune cells.It is a cofactor for several enzymes,has antioxidant activity,and is an epigenetic modifier.Here,we investigated the effects of vitamin C(VC)and its more stable derivative,L-ascorbic acid 2-phosphate(pVC),on the proliferation and effector function of humanγδT cells stimulated with zoledronate(ZOL)or synthetic phosphoantigens(pAgs).VC and pVC did not increaseγδT-cell expansion within ZOL-or pAg-stimulated PBMCs,but increased the proliferation of purifiedγδT cells and 14-day-expandedγδT-cell lines in response toγδT-cell-specific pAgs.VC reduced the apoptosis ofγδT cells during primary stimulation.While pVC did not prevent activation-induced death of pAg-restimulatedγδT cells,it enhanced the cell cycle progression and cellular expansion.Furthermore,VC and pVC enhanced cytokine production during primary activation,as well as upon pAg restimulation of 14-day-expandedγδT cells.VC and pVC also increased the oxidative respiration and glycolysis ofγδT cells,but stimulus-dependent differences were observed.The modulatory activity of VC and pVC might help to increase the efficacy ofγδT-cell expansion for adoptive immunotherapy.
