Role ofγδT cells in liver diseases and its relationship with intestinal microbiota

γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be present at different locations,including the liver,epithelial layer of the gut,the dermis and so on.Many of these cells perform specific functions in liver diseases,such as viral hepatitis,autoimmune liver diseases,non-alcoholic fatty liver disease,liver cirrhosis and liver cancers.In this review,we discuss the distribution,subsets,functions ofγδT cells and the relationship between the microbiota andγδT cells in common hepatic diseases.AsγδT cells have been used to cure hematological and solid tumors,we are interested inγδT cell-based immunotherapies to treat liver diseases.

Nature products of traditional Chinese medicine provide new ideas in γδT cells for tumor immunotherapy

Due to the unique features of innate immune cells, the role of γδT cells in tumor immunity has gradually attracted more and more attention. Previous studies have found that γδT cells play a dual role in tumor immunology: tumor-promoting and tumor-controlling.The anti-tumor therapy of γδT cells has made remarkable success in clinical application. Especially in recent years, researchers have provided some novel effective ways such as γδT cells exosomes and adoptive chimeric antigen receptor-γδT cells immunotherapy. However, some problems remain to be solved, such as low expansion rate, poor targeting, and tumor microenvironment limiting the effectiveness of γδT immunotherapy. Traditional Chinese medicine is expected to play a positive role in the body immune-enhancing function, promoting the proliferation and activation of γδT cells, and inducing the differentiation ofγδT cells. In this review, we summarize the recent research progress and urgent problems of γδT cells in anti-tumor immunotherapy. Moreover, some new strategies of γδT cells for tumor immunotherapy were proposed.

The interaction of dendritic cells and γδ T cells promotes the activation of γδ T cells in experimental autoimmune uveitis

Uveitis is a severe inflammatory disease that can cause visual impairment.Recently,activatedγδT cells were proved to play a central role in the development of experimental autoimmune uveitis(EAU).However,the mechanism underlyingγδT cell activation in EAU is incompletely known.In this study,we determined the percentage changes in and the phenotypes ofγδT cells and dendritic cells(DCs)obtained from the spleens of immunized C57BL/6(B6)mice,an animal model of EAU.We found that the number ofγδT cells and DCs obviously increased during the inflammation phase of EAU(days 16-20 of our experiment),and that during this time,γδT cells expressed high levels of CD69 and the integrin lymphocyte function-associated antigen-1(LF A-1)and secreted high levels of interleukin(IL)-17A.Moreover,DCs obtained during this phase expressed high levels of CD80,CD83,CD86,and intracellular cell adhesion molecule-1(ICAM-1).Furthermore,we studied the interaction between DCs andγδT cells by using flow cytometry and confocal microscopy in order to determine whether DCs affectedγδT-cell activation in vitro.Co-cultures of the two types of cells showed that DCs induced high levels of CD69,LFA-1,and I-17A inγδT cells.Imaging studies revealed contact between the DCs andγδT cells.This interaction was mediated by the accumulation of ICAM-1 and LFA-1 at the interface of DCs-γδT cells.Thus,the activation ofγδT cells in EAU was promoted by DCs interacting withγδT cells.

Adenosine 2A receptor contributes to the facilitation of postinfectious irritable bowel syndrome by γδ T cells via the PKA/CREB/NF-κB signaling pathway

BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome(PI-IBS).γδT cells play a crucial role in innate and adaptive immunity.Adenosine receptors expressed on the surface ofγδT cells participate in intestinal inflammation and immunity regulation.AIM To investigate the role ofγδT cell regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS The PI-IBS mouse model has been established with Trichinella spiralis(T.spiralis)infection.The intestinal A2AR and A2AR inγδT cells were detected by immunohistochemistry,and the inflammatory cytokines were measured by western blot.The role of A2AR on the isolatedγδT cells,including proliferation,apoptosis,and cytokine production,were evaluated in vitro.Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction(RT-PCR).The animals were administered with A2AR agonist,or A2AR antagonist.Besides,γδT cells were also injected back into the animals,and the parameters described above were examined,as well as the clinical features.Furthermore,the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.RESULTS PI-IBS mice exhibited elevated ATP content and A2AR expression(P<0.05),and suppression of A2AR enhanced PI-IBS clinical characteristics,indicated by the abdominal withdrawal reflex and colon transportation test.PI-IBS was associated with an increase in intestinal T cells,and cytokine levels of interleukin-1(IL-1),IL-6,IL-17A,and interferon-α(IFN-α).Also,γδT cells expressed A2AR in vitro and generated IL-1,IL-6,IL-17A,and IFN-α,which can be controlled by A2AR agonist and antagonist.Mechanistic studies demonstrated that the A2AR antagonist improved the function ofγδT cells through the PKA/CREB/NF-κB signaling pathway.CONCLUSION Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function ofγδT cells via the PKA/CREB/NF-κB signaling pathway.

Single-cell RNA-seq and chromatin accessibility profiling decipher the heterogeneity of mouseγδT cells

The distinct characteristics ofγδT cells determine their vital roles in the formation of local immune responses and contribute to tissue homeostasis.However,the heterogeneity ofγδT cells across tissues remains unclear.By combining transcriptional and chromatin analyses with a truly unbiased fashion,we constructed a single-cell transcriptome and chromatin accessibility landscape of mouseγδT cells in the lymph,spleen,and thymus.We also revealed the heterogeneity ofγδT1 andγδT17 cells across these tissues and inferred their potential regulatory mechanisms.In the thymus,we reconstructed the developmental trajectory and gained further insights into the signature genes from the mature stage,intermediate stage,and immature stage ofγδT cells on the basis of single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing data.Notably,a novel Gzma^(+)γδT cell subset was identified with immature properties and only localized to the thymus.Finally,NR1 D1,a circadian transcription factor(TF),was validated as a key and negative regulator ofγδT17 cell differentiation by performing a combined analysis of TF motif enrichment,regulon enrichment,and Nr1 d1 knockout mice.In summary,our data represent a comprehensive mapping on the transcriptome and chromatin accessibility dynamics of mouseγδT cells,providing a valuable resource and reference for future studies onγδT cells.

TOX deficiency facilitates the differentiation of IL-17A-producingγδT cells to drive autoimmune hepatitis

The specification of theαβ/γδlineage and the maturation of medullary thymic epithelial cells(mTECs)coordinate central tolerance to self-antigens.However,the mechanisms underlying this biological process remain poorly clarified.Here,we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation,promoted thymic IL-17A-producingγδT-cell(Tγδ17)lineage commitment,and led to the development of fatal autoimmune hepatitis(AIH)via different mechanisms.Transfer ofγδT cells from TOX-deficient mice reproduced AIH.TOX interacted with and stabilized the TCF1 protein to maintain the balance ofγδT-cell development in thymic progenitors,and overexpression of TCF1 normalizedαβ/γδlineage specification and activation.In addition,TOX expression was downregulated inγδT cells from AIH patients and was inversely correlated with the AIH diagnostic score.Our findings suggest multifaceted roles of TOX in autoimmune control involving mTEC and Tγδ17 development and provide a potential diagnostic marker for AIH.

Expression of PD1 and BTLA on the CD8^+T Cell and γδT Cell Subsets in Peripheral Blood of Non-Small Cell Lung Cancer Patients

Objective To investigate the expression and regulation of programmed cell death protein 1(PD1),B lymphocyte and T lymphocyte attenuator(BTLA)in peripheral blood of patients with non-small cell lung cancer(NSCLC);to examine the correlation of the mRNA levels between PD and BTLA in NSCLC.Methods Flow cytometry was used to detect the expression of PD1 and BTLA on the surfaces of CD8^+T cells andγδ+T cells in the peripheral blood samples collected from 32 in-patients with stage IV NSCLC and 30 healthy individuals.We compared the expression of PD1 and BTLA on the surfaces ofγδ+T cells in the NSCLC patients with bone metastasis before and after the treatment of zoledronic acid.The correlations of PD1 and BTLA,as well as their ligands were analyzed using Pearson correlation analysis with the cBioPortal data platform.Results The frequency of PD1 on the surfaces of CD8^+T cells was significantly higher than that of theγδT cells in both healthy controls(t=2.324,P=0.024)and NSCLC patients(t=2.498,P=0.015).The frequency of PD1 on CD8^+T cells,rather than onγδ+T cells,was significantly upregulated in advanced NSCLC patients compared with that in healthy controls(t=4.829,P<0.001).The PD1+BTLA+γδT cells of the healthy controls were significantly lower than that of the NSCLC patients(t=2.422,P=0.0185).No differences in percentage of PD1+γδ+and BTLA+γδ+T cells were observed in 7 NSCLC patients with bone metastasis before and after zoledronic acid treatment.PD1 was positively correlated with BTLA in both lung adenocarcinoma(r=0.54;P<0.05)and lung squamous cell carcinoma(r=0.78;P<0.05).Conclusions The upregulation of co-inhibitory molecules occurs on the surfaces of both CD8^+T cells andγδT cells in advanced NSCLC,suggesting that these molecules were involved in regulating the inactivation of CD8^+T cells andγδ+T cells,immune escape and tumor invasion.

Immune Regulatory Networks and Therapy of yδT Cells in Liver Cancer:Recent Trends and Advancements

The roles of γδ T cells in liver cancer,especially in the poten-tial function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines,have aroused research interest.This re-view briefly describes the basic characteristics of γδ T cells,focusing on their diverse effects on liver cancer.In particular,different subtypes of γδ T cells have diverse or even opposite effects on liver cancer.We provide a detailed description of the immune regulatory network of γδ T cells in liver can-cer from two aspects:immune components and nonimmune components.The interactions between various components in this immune regulatory network are dynamic and pluralis-tic,ultimately determining the biological effects of γδ T cells in liver cancer.We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment,emphasiz-ing the potential of these cells in liver cancer immunotherapy.

Short-chain fatty acids ameliorate spinal cord injury recovery by regulating the balance of regulatory T cells and effector IL-17^(+) γδ T cells

Spinal cord injury(SCI)causes motor,sensory,and autonomic dysfunctions.The gut microbiome has an important role in SCI,while short-chain fatty acids(SCFAs)are one of the main bioactive mediators of microbiota.In the present study,we explored the effects of oral administration of exogenous SCFAs on the recovery of locomotor function and tissue repair in SCI.Allen’s method was utilized to establish an SCI model in Sprague-Dawley(SD)rats.The animals received water containing a mixture of 150 mmol/L SCFAs after SCI.After 21 d of treatment,the Basso,Beattie,and Bresnahan(BBB)score increased,the regularity index improved,and the base of support(BOS)value declined.Spinal cord tissue inflammatory infiltration was alleviated,the spinal cord necrosis cavity was reduced,and the numbers of motor neurons and Nissl bodies were elevated.Enzyme-linked immunosorbent assay(ELISA),real-time quantitative polymerase chain reaction(qPCR),and immunohistochemistry assay revealed that the expression of interleukin(IL)-10 increased and that of IL-17 decreased in the spinal cord.SCFAs promoted gut homeostasis,induced intestinal T cells to shift toward an anti-inflammatory phenotype,and promoted regulatory T(Treg)cells to secrete IL-10,affecting Treg cells and IL-17^(+)γδT cells in the spinal cord.Furthermore,we observed that Treg cells migrated from the gut to the spinal cord region after SCI.The above findings confirm that SCFAs can regulate Treg cells in the gut and affect the balance of Treg and IL-17^(+)γδT cells in the spinal cord,which inhibits the inflammatory response and promotes the motor function in SCI rats.Our findings suggest that there is a relationship among gut,spinal cord,and immune cells,and the“gut-spinal cord-immune”axis may be one of the mechanisms regulating neural repair after SCI.

Vitamin C promotes the proliferation and effector functions of human γδ T cells

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.

Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-γ-producing γδ T cells

γδ T cells are heterogeneous lymphocytes located in various tissues.However,a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved.In this study,we performed single-cell RNA sequencing(scRNA-seq)to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples.We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors(pre-γδ T cells).The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments.The adoptive transfer of hematopoietic progenitor Lin^(-)Sca-1^(+)Mac-1^(+)(LSM)cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma^(+)(IFN-γ^(+))but not interleukin-17a^(+)(IL-17a^(+))γδ T cells in the liver.Importantly,thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner.These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells,which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.

A Defective CXCL16/CXCR6 Axis Increases the Risk of Pregnancy Loss via the Abnormal Crosstalk between Decidual γδ T Cells and Trophoblasts

Objective::The maternal-fetal interface undergoes dynamic changes to allow the fetus to grow and develop in the uterus.The interaction between decidualγδT cells and trophoblasts plays a pivotal role during successful pregnancy;however,their physiological functions in early-term human pregnancy are still not completely illustrated.This study was undertaken to illustrate the functional roles of CXCL16/CXCR6 to prevent pregnancy loss via the crosstalk between decidualγδT cells and HTR8/SVneo trophoblast cells.Methods::The percentile of CXCR6+γδT cells in the peripheral blood from normal female and recurrent spontaneous abortion(RSA)patients was analyzed by flow cytometry.The expression of CXCR6 was detected in decidual immune cells via flow cytometry,and the expression of CXCL16 was analyzed in HTR8/SVneo trophoblast cells and lentivirus(LV)-HTR8/SVneo trophoblast cells via enzyme-linked immunosorbent assay.Reverse transcriptase-polymerase chain reaction was used to verify the expression of the CXCL16 gene in LV-HTR8/SVneo trophoblast cells.Expression of granzyme B and cytokines and proliferation of decidualγδT cocultured with HTR8/SVneo trophoblast cells were analyzed by flow cytometry.Invasion of HTR8/SVneo trophoblast cells was assessed via Matrigel transwell assay.Adoptive transfer was induced in vivo further to illustrate that the normal expression of CXCL16/CXCR6 could prevent pregnancy loss.Results::The percentile of CXCR6+γδT cells in the peripheral blood from RSA patients was lower than normal pregnancies.The expression of CXCR6 was highest in the decidualγδT cells among decidual immune cells,and the expression of CXCL16 increased as the amount of HTR8/SVneo trophoblast cells increased.Expression of granzyme B in the decidualγδT cells was downregulated by cocultured with HTR8/SVneo cells dependent of CXCL16,and HTR8/SVneo trophoblast cells induced the Th2 cytokines production in the decidualγδT cells.Both the expression of CXCR6 in the decidualγδT cells and proliferation of the decidualγδT cells were promoted by HTR8/SVneo trophoblast cells.On the other hand,decidualγδT cells enhanced the invasion of HTR8/SVneo trophoblast cells and thus promoted embryo implantation.In vivo study was taken further and shown that low expression of CXCL16/CXCR6 results in pregnancy loss because of dialog disorder between decidualγδT cells and trophoblasts.Conclusions::Low expression of CXCL16/CXCR6 results in pregnancy loss because of the dialog disorder between decidualγδT cells and trophoblasts,and it showed a light on the effective strategy of adoptive transfer of CXCR6+γδT cells on the treatment of RSA.This observation provides a scientific basis on which a potential strategy can be applied to the early-detect and treatment of RSA.

Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis

γδT cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity.However,the metabolic requirements and regulation ofγδT-cell development and function remain poorly understood.In this study,we investigated the role of liver kinase B1(Lkb1),a serine/threonine kinase that links cellular metabolism with cell growth and proliferation,inγδT-cell biology.Our findings demonstrate that Lkb1 is not only involved in regulatingγδT lineage commitment but also plays a critical role inγδT-cell effector function.Specifically,T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations inγδT-cell subsets in both the thymus and peripheral lymphoid tissues.Notably,loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4γδT cells,promoted the maturation of IL-17-producing Vγ6γδT cells,and led to the occurrence of fatal autoimmune hepatitis(AIH).Notably,clearance ofγδT cells or blockade of IL-17 significantly attenuated AIH.Mechanistically,Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity,accompanied by increased mTORC1 activation,thereby causing overactivation ofγδT cells and enhanced apoptosis.Interestingly,activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice.Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis ofγδT cells and preventing IL-17-mediated autoimmune diseases,providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymicγδT cells.

Antigen-presenting effects of effector memory Vγ9Vδ2 T cells in rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of γδ2 cells and their relationship with rheumatoid arthritis development. We found that Vγ9Vδ2 T cells （the predominant subtype of γδ T cells in peripheral blood） were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory Vγ9Vδ2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These Vγ9Vδ2 T cells could present soluble antigens and synthetic peptides to CD4＋ T cells. Vγ9Vδ2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memoryVγ9Vδ2 T cells simultaneously secreted not only interferon （IFN）-γbut also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous γδ T cells that were predominantly effector memory Vγ9Vδ2 T cells with the ability to secrete inflammatory factors. We also found that γδ T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, 78 T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, γδ T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4＋ T cells, thus sustaining CD4＋ T-cell activation.

Respective IL-17A production by γδ T and Th17 cells and its implication in host defense against chlamydial lung infection

The role of IL-17A is important in protection against lung infection with Chlamydiae,an obligate intracellular bacterial pathogen.In this study,we explored the producers of IL-17A in chlamydial lung infection and specifically tested the role of major IL-17A producers in protective immunity.We found thatγδT cells and Th17 cells are the major producers of IL-17A at the early and later stages of chlamydial infection,respectively.Depletion ofγδT cells in vivo at the early postinfection(p.i.)stage,when mostγδT cells produce IL-17A,failed to alter Th1 responses and bacterial clearance.In contrast,the blockade of IL-17A at the time when IL-17A was mainly produced by Th17(day 7 p.i.)markedly reduced the Th1 response and increased chlamydial growth.The data suggest that theγδT cell is the highest producer of IL-17A in the very early stages of infection,but the protection conferred by IL-17A is mainly mediated by Th17 cells.In addition,we found that depletion ofγδT cells reduced IL-1αproduction by dendritic cells,which was associated with a reduced Th17 response.This finding is helpful to understand the variable role of IL-17A in different infections and to develop preventive and therapeutic approaches against infectious diseases by targeting IL-17A.

Distortion of memory Vδ2 γδ T cells contributes to immune dysfunction in chronic HIV infection

γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus （HIV） infection disrupts the balance between Vδ1 T cells and Vδ2 T cells and causes dysfunction among γδ T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory γδ T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory Vδ2 γδ T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA Vδ2 γδT cell, which may account for the dysfunction of Vδ2 γδT cells in HIV disease. In addition, we found that IL-17-producing γδ T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR＋ γδ T cells and CD38＋HLA-DR＋ γδ T cells. This suggests the IL-17 signaling pathway is involved in γδ T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of Vδ2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.

The Role of Innate Immune Cells in the Response of Heat-Treated Mycobacterium tuberculosis (M.tb) Antigens Stimulating PBMCs

The proliferation response of γδT cells to the antigen from heat-treated Mycobacterium tuberculosis H37Ra (M.tb Ag)was used as a good model in γδT cell research.From preliminary research it is found that activated NK cells positively elevated γδT cells proliferation after simulating PBMCs with M.tb Ag.To investigate different behaviors of NK cells,γδNKT cells,γδT cells and relationships between these cell subsets,activation and proliferation of different cell subsets of PBMCs in response to M.tb Ag were analyzed.We demonstrated that NK cells,γδNKT cells and γδT cells could be activated after stimulation with M.tb Ag.γδNKT cells and γδT cells proliferated while the number of NK cells decreased after 11 day-simulation with M.tb Ag.Meanwhile,at the early time of stimulation the cytotoxicity of PBMCs was enhanced.Cellular & Molecular Immunology. 2004;1(6):467-470.

Distinct Pattern of Human Vδ/51 γδ/5 T Cells Recognizing MICA

γδ T cells represent one unique recognition pattern, the limited recognition, which distinguishes from the specific recognition for αβ T cells and pattern recognition for macrophages. Vδ1 γδT cell is the major subset of human γδT cells, which predominates in mucosal tissue including the intestinal epithelia. Presently, a few antigens that human Vδ1TCR can recognize have been identified. Among them, MHC class I chain-related molecules A （MICA） have been studied most intensively. Besides Vδ1TCR, MICA is also the ligand of NKG2D, a C-type lectin-like activating immunoreceptor. In human, only Vδ1 cells can simultaneously express both types of receptors of MICA while NK cells, αβ T cells and other subsets of γδT cells likewise express NKG2D. Although the precise mechanisms are still enigmatic, this distinct pattern of Vδ1 cells recognizing MICA predicts unique biological significance of Vδ1 cells in immune defense. Recent years, some progresses have been made in this issue. In this review we summarize the related reports and put forward some novel views based on our group＇s studies.

Human γδT-cell subsets and their involvement in tumor mmunity

γδT cells are a conserved population of innate lymphocytes with diverse structural and functional heterogeneity that participate in various immune responses during tumor progression. γδT cells perform potent immunosurveillance by exerting direct cytotoxicity, strong cytokine production and indirect antitumor immune responses. However, certain γδT-cell subsets also contribute to tumor progression by facilitating cancer-related inflammation and immunosuppression. Here, we review recent observations regarding the antitumor and protumor roles of major structural and functional subsets of human γδT cells, describing how these subsets are activated and polarized, and how these events relate to subsequent function in tumor immunity. These studies provide insights into the manipulation of γδT-cell function to facilitate more targeted approaches for tumor therapy.

Glucose metabolism controls humanγδ-cell-mediated tumor immunosurveillance in diabetes

Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induced Warburg effect type of bioenergetic profle in Vy9vδ2 T cells,leading to excessive lactate accumulation,which further inhibited lytic granule secretion by impairing the traffcking of cytolytic machinery to the Vy9vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro,in vivo and in patients.Strikingly,activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vy9vδ2 T cells.These results suggest that the impaired antitumor activity of Vy9vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.