BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SO...BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SOT,PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism.CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma(DLBCL)with significantly decreased T-cell chimerism early after allo-HCT.A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission.Nearly 3 mo after transplantation,the patient developed cervical lymph node enlargement and gastric lesions,both of which were pathologically suggestive of DLBCL.Meanwhile,the patient experienced a significant and persistent decrease in T-cell chimerism.A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy.CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.展开更多
Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role ...Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.展开更多
Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsucc...Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.Methods:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints.Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized mice.The human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and cytokines.To fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 days.Then,human T cells were processed for TCRβ-chain(TRB)sequencing analysis.After the repertoires had been constructed,features such as the fraction,diversity,and immune signature were investigated.Results:The results demonstrated an increase in diversity and clonality of T cells after treatment.The preferential usage and features of TRBV,TRBJ,and the V–J combination were also changed.The stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 expansion.Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.Conclusions:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools.Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.It therefore has the potential to greatly benefit cancer treatment.展开更多
γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unc...γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unclear.However,in recent years,with the rapid development of tumor immunotherapy,γδT cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex(MHC)restriction.An increasing number of basic studies have focused on the development,antigen recognition,activation,and antitumor immune response ofγδT cells.Additionally,γδT cell-based immunotherapeutic strategies are being developed,and the number of clinical trials investigating such strategies is increasing.This review mainly summarizes the progress of basic research and the clinical application ofγδT cells in tumor immunotherapy to provide a theoretical basis for further the development ofγδT cell-based strategies in the future.展开更多
Human immunodeficiency virus(HIV)has had an insightful impact about the state of healthiness of human immune system.Due to great improvement in drug therapy,HIV infections have been reduced by 17%over the past eight y...Human immunodeficiency virus(HIV)has had an insightful impact about the state of healthiness of human immune system.Due to great improvement in drug therapy,HIV infections have been reduced by 17%over the past eight years.It has been proved that most effective treatment HAART(Highly Active Anti Retroviral Therapy)mainly controls the diseases progression but it does not eradicate the diseases completely.Reverse Transcriptase Inhibitor drugs specially associated with virus specific Cytotoxic T-Lymphocyte(CTL)that declines with disease progression. CTL responses against AIDS pathogenesis could be potential in the dynamics of virus replication, recognition and clearance of infected cells.In this research article a mathematical model has been proposed on the basis of CTL response suppression in the chronic phase of infection due to presence of virus.We also consider the growth of the virus population from the infected CD4^+T cells budding process and from the other infected cells like macrophages and thymocytes.Our analytical and numerical studies are consistent with existing observations from allied areas.展开更多
The involvement of T-lymphocytes in the pathogenesis of myelodysplastic syndromes(MDS) is now well documented by relevant clinical and experimental findings.This brief review will focus on the T-cell repertoire patter...The involvement of T-lymphocytes in the pathogenesis of myelodysplastic syndromes(MDS) is now well documented by relevant clinical and experimental findings.This brief review will focus on the T-cell repertoire pattern typical of MDS patients as well as on the potential role exerted by specific T-cell subsets in this context.Future investigations should further explore the specific role played by different T-cell subsets in the bone marrow milieu typical of MDS, further clarifying which of the described changes represent either an epiphenomenon or rather a real causative factor in the pathogenesis of these disorders.展开更多
T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCR- engineered T cells began more than two decades ago, w...T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCR- engineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCR- engineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.展开更多
CD8^(+)T cells play a central role in antiviral immune responses.Upon infection,naive CD8^(+)T cells differentiate into effector cells to eliminate virus-infected cells,and some of these effector cells further differe...CD8^(+)T cells play a central role in antiviral immune responses.Upon infection,naive CD8^(+)T cells differentiate into effector cells to eliminate virus-infected cells,and some of these effector cells further differentiate into memory cells to provide long-term protection after infection is resolved.Although extensively investigated,the underlying mechanisms of CD+T-cell differentiation remain incompletely understood.Themis is a T-cell-specific protein that plays critical roles in T-cell development.Recent studies using Themis T-cell conditional knockout mice also demonstrated that Themis is required to promote mature CD8^(+)T-cell homeostasis,cytokine responsiveness,and antibacterial responses.In this study,we used LCMV Armstrong infection as a probe to explore the role of Themis in viral infection.We found that preexisting CD8^(+)T-cell homeostasis defects and cytokine hyporesponsiveness do not impair viral clearance in Themis T-cell conditional knockout mice.Further analyses showed that in the primary immune response,Themis deficiency promoted the differentiation of CD8^(+)effector cells and increased their TNF and IFNy production.Moreover,Themis deficiency impaired memory precursor cell(MPEC)differentiation but promoted short-lived effector cell(SLEC)differentiation.Themis deficiency also enhanced effector cytokine production in memory CD8^(+)T cells while impairing central memory CD8^(+)T-cell formation.Mechanistically,we found that Themis mediates PD-1 expression and its signaling in effector CD8^(+)T cells,which explains the elevated cytokine production in these cells when Themis is disrupted.展开更多
Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been show...Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) at doses of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine (IFN-7, IL-2 and TNF-a) production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenesexpressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.展开更多
In the last two decades, it has become clear that yo T cells recognize a diverse array of antigens including self and foreign, large and small, and peptidic and non-peptidic molecules. In this respect, 78 antigens as ...In the last two decades, it has become clear that yo T cells recognize a diverse array of antigens including self and foreign, large and small, and peptidic and non-peptidic molecules. In this respect, 78 antigens as a whole resemble more the antigens recognized by antibodies than those recognized by T cells. Because of this antigenic diversity, no single mechanism--such as the major histocompatibility complex (MHC) restriction of ap T cells--is likely to provide a basis for all observed T-cell antigen receptor (TCR)-dependent 78 T-cell responses. Furthermore, available evidence suggests that many individual 78 T cells are poly-specific, probably using different modes of ligand recognition in their responses to unrelated antigens. While posing a unique challenge in the maintenance of self-tolerance, this broad reactivity pattern might enable multiple overlapping uses of 78 T-cell populations, and thus generate a more efficient immune response.展开更多
Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical b...Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical basic for new treatment of unexplained abortion.Methods:Flow cytometry(FCM)was used to detect the expression of AHR in peripheral/decidual CD4+T,Treg,and Th17 cells.The effect of Kyn on the differentiation of peripheral/decidual naïve T-cells under Treg-/Th17-polarizing condition was detected by FCM;enzyme-linked immunosorbent assay was performed to examine the level of Kyn in villus and decidual tissues from normal pregnancy(NP)and unexplained abortion(UA).Student’s t-test in the case of two groups or one-way ANOVA in multiple groups was used.Results:AHR expression in CD4+T-cells was decreased in decidua versus blood in early pregnancy(P<0.0001).Kyn could promote the differentiation of peripheral and decidual naïve T-cells to Th17 cells under Treg-polarizing conditions(P<0.01).There was no statistical significance about the concentration of Kyn in decidual or villi tissues between NP and UA,and compared with NP,the expression of AHR in decidual CD4+T-cells from UA was increased(P<0.001).Conclusions:Kyn/AHR promotes Th17 and restricts Treg cells’differentiation,which is involved in maintaining the balance of Treg/Th17 cells at the maternal-fetal interface.展开更多
Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (γδ) T cells remains u...Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (γδ) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of γδ T cells and the balance between variable delta 1 (Vδ1) and Vδ2 T cells in humans. The results show that I L-4 inhibits the activation of y8 T cells in the presence of γδ T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated γδ T cells and increased the levels of Vδ1 T cells, which in turn inhibited V82 T-cell growth via significant IL-10 secretion. VδI T cells secreted significantly less interferon gamma (IFNy) and more IL-10 relative to Vδ2. Furthermore, Vδ1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vδ1 T cells weaken the γδ T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in γδ T cell-mediated anti-tumor immunity.展开更多
Vy2Vδ2 T (also known as Vy9Vδ2 T) cells exist only in primates, and in humans represent a major yδ T-cell sub-population in the total population of circulating yδ T cells. Results from recent studies suggest tha...Vy2Vδ2 T (also known as Vy9Vδ2 T) cells exist only in primates, and in humans represent a major yδ T-cell sub-population in the total population of circulating yδ T cells. Results from recent studies suggest that while (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen from Mycobacterium tuberculosis (Mtb) and other microbes activates and expands primate Vy2Vδ2 T cells, the Vy2Vδ2 T-cell receptor (TCR) recognizes and binds to HMBPP on antigen-presenting cells (APC). In response to HMBPP stimulus, Vy2V82 TCRs array to form signaling-related nanoclusters or nanodomains during the activation of Vy2V82 T cells. Primary infections with H MBPP-producing pathogens drive the evolution of multieffector functional responses in Vy2Vδ2 T cells, although Vy2V82 T cells display different patterns of responses during the acute and chronic phases of Mtb infection and in other infections. Expanded Vy2Vδ2 T cells in primary Mtb infection can exhibit a broader TCR repertoire and a greater clonal response than previously assumed, with different distribution patterns of Vδ,2Vδ2 T-cell clones in lymphoid and non-lymphoid compartments. Emerging in vivo data suggest that HMBPP activation of Vy2W2 T cells appears to impact other immune cells during infection.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
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
Phenotypic and functional heterogeneity are the hallmarks of effector and memory T cells. Upon antigen stimulation, y T cells differentiate into two major types of memory T cells: central memory cells, which patrol t...Phenotypic and functional heterogeneity are the hallmarks of effector and memory T cells. Upon antigen stimulation, y T cells differentiate into two major types of memory T cells: central memory cells, which patrol the blood and secondary lymphoid organs, and effector memory cells, which migrate to peripheral tissues, y T cells display in vitroa certain degree of plasticity in their function that is reminiscent of that which is observed in conventional CD4 T cells. Similar to CD4 T cells, in which a plethora of specialized subsets affect the host response, y8 T cells may readily and rapidly assume distinct Thl-, Th2-, Th17-, TFH and T regulatory-like effector functions, suggesting that they profoundly influence cell-mediated and humoral immune responses. In addition to differences in cytokine repertoire, y~ T cells exhibit diversity in homing, such as migration to lymph node follicles, to help B cells versus migration to inflamed tissues. Here, we review our current understanding of y T-cell lineage heterogeneity and flexibility, with an emphasis on the human system, and propose a classification of effector y T cells based on distinct functional phenotypes.展开更多
The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not complet...The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not completely known.Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells,such as immune presenting cells or tumor cells.In this study,we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs,involving their TCR and the butyrophilins BTN3A1 and BTN2A1.This is the first time that these three molecules,concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells,have been shown to be involved together on the same and unique T cell during PAg activation.Moreover,the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed byγ9TCR,BTN3A1 and BTN2A1.The self-activation of Vγ9Vδ2 T cells,which leads to self-killing,can therefore participate in the failure ofγδT cell-based therapies with exogenous PAgs and should be taken into account.展开更多
CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encou...CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen,which induces these cells to proliferate and differentiate into effector cells that fight the initial infection.Simultaneously,a fraction of these cells become long-lived memory CD8^(+)T cells that combat future infections.Notably,the generation and maintenance of memory cells is profoundly affected by various in vivo conditions,such as the mode of primary activation(e.g.,acute vs.chronic immunization)or fluctuations in host metabolic,inflammatory,or aging factors.Therefore,many T cells may be lost or become exhausted and no longer functional.Complicated intracellular signaling pathways,transcription factors,epigenetic modifications,and metabolic processes are involved in this process.Therefore,understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8^(+)cells is central for harnessing cellular immunity.In this review,we focus on mammalian target of rapamycin(mTOR),particularly signaling mediated by mTOR complex(mTORC)2 in memory and exhausted CD8^(+)T cells at the molecular level.展开更多
Although lymphocytes are known to circulate throughout lymphoid tissues and blood,they also establish residency in nonlymphoid organs,most prominently in barrier tissues,such as the intestines.The adaptation of T lymp...Although lymphocytes are known to circulate throughout lymphoid tissues and blood,they also establish residency in nonlymphoid organs,most prominently in barrier tissues,such as the intestines.The adaptation of T lymphocytes to intestinal environments requires constant discrimination between natural stimulation from commensal flora and food and pathogens that need to be cleared.Genetic variations that cause a defective defense or a break in tolerance along with environmental cues,such as infection or imbalances in the gut microbiota known as dysbiosis,can trigger several immune disorders via the activation of T lymphocytes in the intestines.Elucidation of the immune mechanisms that distinguish between commensal flora and pathogenic organisms may reveal therapeutic targets for the prevention or modulation of inflammatory diseases and boost the efficacy of cancer immunotherapy.In this review,we discuss the development and adaptation of T lymphocytes in the intestine,how these cells protect the host against pathogenic infections while tolerating food antigens and commensal microbiota,and the potential implications of targeting these cells for disease management and therapeutics.展开更多
文摘BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SOT,PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism.CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma(DLBCL)with significantly decreased T-cell chimerism early after allo-HCT.A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission.Nearly 3 mo after transplantation,the patient developed cervical lymph node enlargement and gastric lesions,both of which were pathologically suggestive of DLBCL.Meanwhile,the patient experienced a significant and persistent decrease in T-cell chimerism.A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy.CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.
基金supported by grants from National Natural Science Foundation of China(Nos.81870140 and 82070184)Peking University People’s Hospital Research and Development Funds(No.RDL2021-01)+1 种基金Beijing Nova Program(No.20220484235)Beijing Life Oasis Public Service Center(No.CARTFR-01)
文摘Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.
基金National Natural Science Foundation of China,Grant/Award Numbers:82130003,81970158,82000180Zhejiang Provincial Key R&D Projects of Department of Science and Technology,Grant/Award Number:2021C03010Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004。
文摘Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.Methods:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints.Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized mice.The human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and cytokines.To fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 days.Then,human T cells were processed for TCRβ-chain(TRB)sequencing analysis.After the repertoires had been constructed,features such as the fraction,diversity,and immune signature were investigated.Results:The results demonstrated an increase in diversity and clonality of T cells after treatment.The preferential usage and features of TRBV,TRBJ,and the V–J combination were also changed.The stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 expansion.Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.Conclusions:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools.Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.It therefore has the potential to greatly benefit cancer treatment.
基金supported by grants from the National Natural Science Foundation of China(Nos.32270915,31970843,82071791,U20A20374,and 81972886)National Key Research and Development Program of China(No.2022YFC3602004)+4 种基金CAMS Initiative for Innovative Medicine(Nos.2021-I2M-1-005,2021-I2M-1-035,and 2021-I2M-1-053)Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00028)CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses(No.3332020035)Changzhou Science and Technology Support Plan(No.CE20215008)Beijing Municipal Commission of Science and Technology Fund for Innovative Drug(No.Z221100007922040)
文摘γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unclear.However,in recent years,with the rapid development of tumor immunotherapy,γδT cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex(MHC)restriction.An increasing number of basic studies have focused on the development,antigen recognition,activation,and antitumor immune response ofγδT cells.Additionally,γδT cell-based immunotherapeutic strategies are being developed,and the number of clinical trials investigating such strategies is increasing.This review mainly summarizes the progress of basic research and the clinical application ofγδT cells in tumor immunotherapy to provide a theoretical basis for further the development ofγδT cell-based strategies in the future.
基金Research is supported by the Government of India,Ministry of Science and Technology,Mathematical Science office,No.SR/S4/MS:558/08
文摘Human immunodeficiency virus(HIV)has had an insightful impact about the state of healthiness of human immune system.Due to great improvement in drug therapy,HIV infections have been reduced by 17%over the past eight years.It has been proved that most effective treatment HAART(Highly Active Anti Retroviral Therapy)mainly controls the diseases progression but it does not eradicate the diseases completely.Reverse Transcriptase Inhibitor drugs specially associated with virus specific Cytotoxic T-Lymphocyte(CTL)that declines with disease progression. CTL responses against AIDS pathogenesis could be potential in the dynamics of virus replication, recognition and clearance of infected cells.In this research article a mathematical model has been proposed on the basis of CTL response suppression in the chronic phase of infection due to presence of virus.We also consider the growth of the virus population from the infected CD4^+T cells budding process and from the other infected cells like macrophages and thymocytes.Our analytical and numerical studies are consistent with existing observations from allied areas.
文摘The involvement of T-lymphocytes in the pathogenesis of myelodysplastic syndromes(MDS) is now well documented by relevant clinical and experimental findings.This brief review will focus on the T-cell repertoire pattern typical of MDS patients as well as on the potential role exerted by specific T-cell subsets in this context.Future investigations should further explore the specific role played by different T-cell subsets in the bone marrow milieu typical of MDS, further clarifying which of the described changes represent either an epiphenomenon or rather a real causative factor in the pathogenesis of these disorders.
文摘T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCR- engineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCR- engineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.
基金the Core Facility of Biomedical Sciences,Xiamen University for Flow Cytometry Cell Sorting service.This study was supported by the National Natural Science Foundation of China(32070887)the Fundamental Research Funds for the Central Universities(20720220003)to G.F.Singapore Ministry of Education(MOE-000112)Singapore Ministry of Health's National Medical Research Council(MOH-000523)to N.RJ.Gascoigne.The Natural Science Foundation of Fujian Province(No.2019J01009)to Q.L.The National Natural Science Foundation of China(U1904206)to X.L.C.The funders had no role in the study design,data collection and analysis,decision to publish,or preparation of the manuscript。
文摘CD8^(+)T cells play a central role in antiviral immune responses.Upon infection,naive CD8^(+)T cells differentiate into effector cells to eliminate virus-infected cells,and some of these effector cells further differentiate into memory cells to provide long-term protection after infection is resolved.Although extensively investigated,the underlying mechanisms of CD+T-cell differentiation remain incompletely understood.Themis is a T-cell-specific protein that plays critical roles in T-cell development.Recent studies using Themis T-cell conditional knockout mice also demonstrated that Themis is required to promote mature CD8^(+)T-cell homeostasis,cytokine responsiveness,and antibacterial responses.In this study,we used LCMV Armstrong infection as a probe to explore the role of Themis in viral infection.We found that preexisting CD8^(+)T-cell homeostasis defects and cytokine hyporesponsiveness do not impair viral clearance in Themis T-cell conditional knockout mice.Further analyses showed that in the primary immune response,Themis deficiency promoted the differentiation of CD8^(+)effector cells and increased their TNF and IFNy production.Moreover,Themis deficiency impaired memory precursor cell(MPEC)differentiation but promoted short-lived effector cell(SLEC)differentiation.Themis deficiency also enhanced effector cytokine production in memory CD8^(+)T cells while impairing central memory CD8^(+)T-cell formation.Mechanistically,we found that Themis mediates PD-1 expression and its signaling in effector CD8^(+)T cells,which explains the elevated cytokine production in these cells when Themis is disrupted.
基金ACKNOWLEDGEMENTS We thank Yingxin Yu (Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering,Shanghai University) for determining the BDE-209 concentration, Nining Guo and Qibing Leng (Institute Pasteur of Shanghai, Chinese Academy of Science) for the rLm-OVA infections and Xing Zhang (College of Public Health, Shanghai Jiaotong University School of Medicine) for breeding the animals. This work is supported by the National Basic Research Program of China (2011CB512104), the 12th Five-Year Plan of National Science and Technology Support (2012BAK17B10) and the National Natural Science Foundation of China (81101252).
文摘Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) at doses of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine (IFN-7, IL-2 and TNF-a) production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenesexpressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.
文摘In the last two decades, it has become clear that yo T cells recognize a diverse array of antigens including self and foreign, large and small, and peptidic and non-peptidic molecules. In this respect, 78 antigens as a whole resemble more the antigens recognized by antibodies than those recognized by T cells. Because of this antigenic diversity, no single mechanism--such as the major histocompatibility complex (MHC) restriction of ap T cells--is likely to provide a basis for all observed T-cell antigen receptor (TCR)-dependent 78 T-cell responses. Furthermore, available evidence suggests that many individual 78 T cells are poly-specific, probably using different modes of ligand recognition in their responses to unrelated antigens. While posing a unique challenge in the maintenance of self-tolerance, this broad reactivity pattern might enable multiple overlapping uses of 78 T-cell populations, and thus generate a more efficient immune response.
基金supported by grants from the Natural Science Foundation of China(No.81373868).
文摘Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical basic for new treatment of unexplained abortion.Methods:Flow cytometry(FCM)was used to detect the expression of AHR in peripheral/decidual CD4+T,Treg,and Th17 cells.The effect of Kyn on the differentiation of peripheral/decidual naïve T-cells under Treg-/Th17-polarizing condition was detected by FCM;enzyme-linked immunosorbent assay was performed to examine the level of Kyn in villus and decidual tissues from normal pregnancy(NP)and unexplained abortion(UA).Student’s t-test in the case of two groups or one-way ANOVA in multiple groups was used.Results:AHR expression in CD4+T-cells was decreased in decidua versus blood in early pregnancy(P<0.0001).Kyn could promote the differentiation of peripheral and decidual naïve T-cells to Th17 cells under Treg-polarizing conditions(P<0.01).There was no statistical significance about the concentration of Kyn in decidual or villi tissues between NP and UA,and compared with NP,the expression of AHR in decidual CD4+T-cells from UA was increased(P<0.001).Conclusions:Kyn/AHR promotes Th17 and restricts Treg cells’differentiation,which is involved in maintaining the balance of Treg/Th17 cells at the maternal-fetal interface.
基金We thank Dr Mingxiao He (Duke University for Immunology Research) for critical reading of this manuscript. This work was supported by the Research Special Fund for Public Welfare Industry of Health (Grant Nos. 201202004 and 201302018), the National Program for Key Basic Research Projects, Ministry of Science and Technology, China (2013CB530503 and 2014CB542103), the Beijing Natural Science Foundation (Grant No. 5122031), the National Natural Science Foundation of China (Grant No. 30972776) and the National High Technology Research and Development Program (863 Program) (Grant No. 2007AA021109). We thank Dr Austin Cape for careful reading and feedback.
文摘Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (γδ) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of γδ T cells and the balance between variable delta 1 (Vδ1) and Vδ2 T cells in humans. The results show that I L-4 inhibits the activation of y8 T cells in the presence of γδ T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated γδ T cells and increased the levels of Vδ1 T cells, which in turn inhibited V82 T-cell growth via significant IL-10 secretion. VδI T cells secreted significantly less interferon gamma (IFNy) and more IL-10 relative to Vδ2. Furthermore, Vδ1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vδ1 T cells weaken the γδ T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in γδ T cell-mediated anti-tumor immunity.
文摘Vy2Vδ2 T (also known as Vy9Vδ2 T) cells exist only in primates, and in humans represent a major yδ T-cell sub-population in the total population of circulating yδ T cells. Results from recent studies suggest that while (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen from Mycobacterium tuberculosis (Mtb) and other microbes activates and expands primate Vy2Vδ2 T cells, the Vy2Vδ2 T-cell receptor (TCR) recognizes and binds to HMBPP on antigen-presenting cells (APC). In response to HMBPP stimulus, Vy2V82 TCRs array to form signaling-related nanoclusters or nanodomains during the activation of Vy2V82 T cells. Primary infections with H MBPP-producing pathogens drive the evolution of multieffector functional responses in Vy2Vδ2 T cells, although Vy2V82 T cells display different patterns of responses during the acute and chronic phases of Mtb infection and in other infections. Expanded Vy2Vδ2 T cells in primary Mtb infection can exhibit a broader TCR repertoire and a greater clonal response than previously assumed, with different distribution patterns of Vδ,2Vδ2 T-cell clones in lymphoid and non-lymphoid compartments. Emerging in vivo data suggest that HMBPP activation of Vy2W2 T cells appears to impact other immune cells during infection.
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.
文摘Phenotypic and functional heterogeneity are the hallmarks of effector and memory T cells. Upon antigen stimulation, y T cells differentiate into two major types of memory T cells: central memory cells, which patrol the blood and secondary lymphoid organs, and effector memory cells, which migrate to peripheral tissues, y T cells display in vitroa certain degree of plasticity in their function that is reminiscent of that which is observed in conventional CD4 T cells. Similar to CD4 T cells, in which a plethora of specialized subsets affect the host response, y8 T cells may readily and rapidly assume distinct Thl-, Th2-, Th17-, TFH and T regulatory-like effector functions, suggesting that they profoundly influence cell-mediated and humoral immune responses. In addition to differences in cytokine repertoire, y~ T cells exhibit diversity in homing, such as migration to lymph node follicles, to help B cells versus migration to inflamed tissues. Here, we review our current understanding of y T-cell lineage heterogeneity and flexibility, with an emphasis on the human system, and propose a classification of effector y T cells based on distinct functional phenotypes.
基金This work was funded by INSERM,CNRS,the University Hospital of Bordeaux,and Toulouse III University.We acknowledge ImCheck for providing the 103.2 antibody and the 7.48 antibody.We are grateful to our healthcare professionals for their boundless efforts during the COVID-19 crisis.
文摘The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not completely known.Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells,such as immune presenting cells or tumor cells.In this study,we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs,involving their TCR and the butyrophilins BTN3A1 and BTN2A1.This is the first time that these three molecules,concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells,have been shown to be involved together on the same and unique T cell during PAg activation.Moreover,the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed byγ9TCR,BTN3A1 and BTN2A1.The self-activation of Vγ9Vδ2 T cells,which leads to self-killing,can therefore participate in the failure ofγδT cell-based therapies with exogenous PAgs and should be taken into account.
基金This work was supported by grants from the National Natural Science Foundation of China(31930035,91942311,and 32061143028 to BS,32200738 to YC32170895 to NW)+5 种基金National Key R&D Program of China(2021YFA1301400 to BS)Shanghai Science and Technology Commission(20410714000,20JC410100,and 22JC1402600 to BS,22ZR1480700,22QA1408000 to NW)Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases to BS,China Postdoctoral Science Foundation(2022T150422 to YC,2021M692127 to HS)Nurture projects for basic research of Shanghai Chest Hospital(2021YNJCQ6 to XO).HS and YC are YuHe Postdoctoral Fellow at Shanghai Institute of ImmunologyYC is also supported by fellowships from Shanghai Postdoctoral Excellence Program(2021250)and China International Postdoctoral Exchange Fellowship Program(Talent-Introduction Program)ZX is supported by the Zhi-Yuan Endowed fund from Shanghai Jiao Tong University.
文摘CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen,which induces these cells to proliferate and differentiate into effector cells that fight the initial infection.Simultaneously,a fraction of these cells become long-lived memory CD8^(+)T cells that combat future infections.Notably,the generation and maintenance of memory cells is profoundly affected by various in vivo conditions,such as the mode of primary activation(e.g.,acute vs.chronic immunization)or fluctuations in host metabolic,inflammatory,or aging factors.Therefore,many T cells may be lost or become exhausted and no longer functional.Complicated intracellular signaling pathways,transcription factors,epigenetic modifications,and metabolic processes are involved in this process.Therefore,understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8^(+)cells is central for harnessing cellular immunity.In this review,we focus on mammalian target of rapamycin(mTOR),particularly signaling mediated by mTOR complex(mTORC)2 in memory and exhausted CD8^(+)T cells at the molecular level.
基金by grants from the National Key R&D Program of China(2018YFA0508000)(S.Z.)the National Natural Science Foundation of China(81822021,91842105,31770990,81788101 and 81821001)(S.Z.),and(81871284)(H.M.)and the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030101)(S.Z.).
文摘Although lymphocytes are known to circulate throughout lymphoid tissues and blood,they also establish residency in nonlymphoid organs,most prominently in barrier tissues,such as the intestines.The adaptation of T lymphocytes to intestinal environments requires constant discrimination between natural stimulation from commensal flora and food and pathogens that need to be cleared.Genetic variations that cause a defective defense or a break in tolerance along with environmental cues,such as infection or imbalances in the gut microbiota known as dysbiosis,can trigger several immune disorders via the activation of T lymphocytes in the intestines.Elucidation of the immune mechanisms that distinguish between commensal flora and pathogenic organisms may reveal therapeutic targets for the prevention or modulation of inflammatory diseases and boost the efficacy of cancer immunotherapy.In this review,we discuss the development and adaptation of T lymphocytes in the intestine,how these cells protect the host against pathogenic infections while tolerating food antigens and commensal microbiota,and the potential implications of targeting these cells for disease management and therapeutics.