Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis

Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/b-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knockdown.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/b-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/b-arrestin2 pathway.Collectively,our study provided a therapeutic mAb,3A5C7,targeting MOR to treat morphine tolerance,mediated by enhancing morphine-induced MOR endocytosis.The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines,anti-PD-1 and poly I:C

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex(MHC)class I and II antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4t and CD8t T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

Modified Therapeutic Antibodies: Improving Efficacy

The prosperity of the biotherapeutics market reflects the feasibility and effectiveness of therapeutic antibodies for the treatment of cancers,inflammatory disorders,and refractory infections.As drawbacks emerge in clinical trials and practice,such as impeded binding,reduced effector functions,and frequent adverse reactions,modifications of therapeutic antibodies are unprecedently burgeoning in research and development(R&D).These modifications include:①modified glycosylation;②fragment of crystallizable domain(Fc)amino acid alterations;③cross-isotype or cross-subclass exchanges;④antibody–drug conjugates(ADCs);⑤single chain of variable region fragment(scFv)for chimeric antigen receptor T(CAR-T)cells;and⑥bispecific antibodies(bsAbs)in order to promote binding affinity,half-life in circulation,effectiveness toward target cells and,ultimately,to achieve overall improved efficacy.While many achievements have been made around the world in the past decades,China has been playing an active role in this realm,with its great demand for biotherapeutics with R&D potential.This review recapitulates the international progress that has been achieved with modified therapeutic antibodies,and then focuses on that of China in an independent section.

Meplazumab in hospitalized adults with severe COVID-19(DEFLECT):a multicenter,seamless phase 2/3,randomized,third-party double-blind clinical trial

Meplazumab,a humanized CD147 antibody,has shown favourable safety and efficacy in our previous clinical studies.In DEFLECT(NCT04586153),167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo.Meplazumab at 0.12 mg/kg,compared to the placebo group,showed clinical benefits in significantly reducing mortality by 83.6%(2.4%vs.14.6%,p=0.0150),increasing the proportion of patients alive and discharged without supplemental oxygen(82.9%vs.70.7%,p=0.0337)and increasing the proportion of patients who achieved sustained clinical improvement(41.5%vs.31.7%).The response rate in the 0.2 mg/kg group was relatively increased by 16.0%compared with the placebo group(53.7%vs.46.3%).Meplazumab also reduced the viral loads and multiple cytokine levels.Compare with the placebo group,the 0.3 mg/kg significantly increased the virus negative rate by 40.6%(p=0.0363)and reduced IL-8 level(p=0.0460);the 0.2 mg/kg increased the negative conversion rate by 36.9%,and reduced IL-4(p=0.0365)and IL-8 levels(p=0.0484).In this study,the adverse events occurred at a comparable rate across the four groups,with no unexpected safety findings observed.In conclusion,meplazumab promoted COVID-19 convalescence and reduced mortality,viral load,and cytokine levels in severe COVID-19 population with good safety profile.

Metabolic interaction:tumor-derived lactate inhibiting CD8^(+)T cell cytotoxicity in a novel route

Recently,an interesting study published in Cell Metabolism discovered a novel metabolic interaction between tumors and T cells,identifying that tumor-derived lactate inhibited CD8^(+)T cell cytotoxicity by inducing a switch of pyruvate utilization from pyruvate carboxylase(PC)to pyruvate dehydrogenase(PDH),and PDH inhibition facilitated PC activity and T cell cytotoxicity through increasing succinate secretion.

HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression

Background The mechanism of hepatitis B virus(HBV)-induced carcinogenesis remains an area of interest.The accumulation of hepatitis B surface antigen in the endoplasmic reticulum(ER)of hepatocytes stimulates persistent ER stress.Activity of the unfolded protein response(UPR)pathway of ER stress may play an important role in inflammatory cancer transformation.How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV-related hepatocellular carcinoma(HCC)is still unclear.Here,we aimed to define the key molecule hyaluronan-mediated motility receptor(HMMR)in this process and explore its role under ER stress in HCC development.Methods An HBV-transgenic mouse model was used to characterize the pathological changes during the tumor progression.Proteomics and transcriptomics analyses were performed to identify the potential key molecule,screen the E3 ligase,and define the activation pathway.Quantitative real-time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines.Luciferase reporter assay,chromatin immunoprecipitation,coimmunoprecipitation,immunoprecipitation,and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress.Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues.Results We found sustained activation of ER stress in the HBV-transgenic mouse model of hepatitis-fibrosis-HCC.HMMR was transcribed by c/EBP homologous protein(CHOP)and degraded by tripartite motif containing 29(TRIM29)after ubiquitination under ER stress,which caused the inconsistent expression of mRNA and protein.Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR.HMMR could alleviate ER stress by increasing autophagic lysosome activity.The negative correlation between HMMR and ER stress,positive correlation between HMMR and autophagy,and negative correlation between ER stress and autophagy were verified in human tissues.Conclusions This study identified the complicated role of HMMR in autophagy and ER stress,that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression,which could be a novel explanation for HBV-related carcinogenesis.

Immunological and metabolic characteristics of the Omicron variants infection

The Omicron variants of SARS-CoV-2,primarily authenticated in November 2021 in South Africa,has initiated the 5th wave of global pandemics.Here,we systemically examined immunological and metabolic characteristics of Omicron variants infection.We found Omicron resisted to neutralizing antibody targeting receptor binding domain(RBD)of wildtype SARS-CoV-2.Omicron could hardly be neutralized by sera of Corona Virus Disease 2019(COVID-19)convalescents infected with the Delta variant.Through mass spectrometry on MHC-bound peptidomes,we found that the spike protein of the Omicron variants could generate additional CD8+T cell epitopes,compared with Delta.These epitopes could induce robust CD8+T cell responses.Moreover,we found booster vaccination increased the cross-memory CD8+T cell responses against Omicron.Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted the response of memory T cells.Consistently,a greater fraction of memory CD8+T cells existed in Omicron stimulated peripheral blood mononuclear cells(PBMCs).In addition,CD147 was also a receptor for the Omicron variants,and CD147 antibody inhibited infection of Omicron.CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia.Taken together,our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2,no specific and effective drugs for treating this disease have been reported until today.Angiotensin-converting enzyme 2(ACE2),a receptor of SARS-CoV-2,mediates the virus infection by binding to spike protein.Although ACE2 is expressed in the lung,kidney,and intestine,its expressing levels are rather low,especially in the lung.Considering the great infectivity of COVID-19,we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection.Here,we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein.The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody,Meplazumab,inhibits SARSCoV-2 amplification.Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells,which can be neutralized by CD147 extracellular fragment.Viral loads are detectable in the lungs of human CD147(hCD147)mice infected with SARS-CoV-2,but not in those of virus-infected wild type mice.Interestingly,virions are observed in lymphocytes of lung tissue from a COVID-19 patient.Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dosedependent manner,which is specifically inhibited by Meplazumab.Furthermore,CD147 mediates virus entering host cells by endocytosis.Together,our study reveals a novel virus entry route,CD147-spike protein,which provides an important target for developing specific and effective drug against COVID-19.

CD147 regulates antitumor CD8^(+)T-cell responses to facilitate tumor-immune escape

Negative regulation of antitumor T-cell-immune responses facilitates tumor-immune escape.Here,we show that deletion of CD147,a type I transmembrane molecule,in T cells,strongly limits in vivo tumor growth of mouse melanoma and lung cancer in a CD8^(+)T-cell-dependent manner.In mouse tumor models,CD147 expression was upregulated on CD8^(+)tumor-infiltrating lymphocytes(TILs),and CD147 was coexpressed with two immune-checkpoint molecules,Tim-3 and PD-1.Mining publicly available gene-profiling data for CD8^(+)TILs in tumor biopsies from metastatic melanoma patients showed a higher level of CD147 expression in exhausted CD8^(+)TILs than in other subsets of CD8^(+)TILs,along with expression of PD-1 and TIM-3.Additionally,CD147 deletion increased the abundance of TILs,cytotoxic effector function of CD8^(+)T cells,and frequency of PD-1^(+)CD8^(+)TILs,and partly reversed the dysfunctional status of PD-1^(+)Tim-3^(+)CD8^(+)TILs.The cytotoxic transcription factors Runx3 and T-bet mediation enhanced antitumor responses by CD147^(-/-)CD8^(+)T cells.Moreover,CD147 deletion in T cells increased the frequency of TRM-like cells and the expression of the T-cell chemokines CXCL9 and CXCL10 in the tumor microenvironment.Analysis of tumor tissue samples from patients with non-small-cell lung cancer showed negative correlations between CD147 expression on CD8^(+)TILs and the abundance of CD8^(+)TILs,histological grade of the tumor tissue samples,and survival of patients with advanced tumors.Altogether,we found a novel function of CD147 as a negative regulator of antitumor responses mediated by CD8^(+)TILs and identified CD147 as a potential target for cancer immunotherapy.

CD 147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

Major gaps in understanding the molecular mechanisms of colorectal cancer(CRC)progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders.Trefoil factor 3(TFF3)has been reported to be involved in CRC progression and intestinal mucosal repair;however,how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood.Here,we found that the upregulated TFF3 in CRC predicted a worse overall survival rate.TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis.CD147,a membrane protein,was identified as a binding partner for TFF3.Via binding to CD147,TFF3 enhanced CD147-CD44s interaction,resulting in signal transducer and activator of transcription 3(STAT3)activation and prostaglandin G/H synthase 2(PTGS2)expression,which were indispensable for TFF3-induced migration,proliferation,and invasion.PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype(PTGER4)and contributed to TFF3-stimulated CRC progression.Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression.The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor.Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice.Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression,which widens and deepens the understanding of the molecular function of trefoil factors.

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta,alpha,beta,and gamma

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape,compromising the effectiveness of existing vaccines and neutralizing antibodies.An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants.Here,we identified CD147 as a universal receptor for SARS-CoV-2 and its variants.Meanwhile,Meplazeumab,a humanized anti-CD147 antibody,could block cellular entry of SARS-CoV-2 and its variants-alpha,beta,gamma,and delta,with inhibition rates of 68.7,75.7,52.1,52.1,and 62.3%at 60μg/ml,respectively.Furthermore,humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants,alpha and beta.When infected,these mice developed exudative alveolar pneumonia,featured by immune responses involving alveoli-infiltrated macrophages,neutrophils,and lymphocytes and activation of IL-17 signaling pathway.Mechanistically,we proposed that severe COVID-19-related cytokine storm is induced by a"spike protein-CD147-CyPA signaling axis":Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway,which further induced expression of cyclophilin A(CyPA);CyPA reciprocally bound to CD147 and triggered MAPK pathway.Consequently,the MAPK pathway regulated the expression of cytokines and chemokines,which promoted the development of cytokine storm.Importantly,Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants.Therefore,our findings provided a new perspective for severe COVID-19-related pathogenesis.Furthermore,the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

UBE2S interacting with TRIM28 in the nucleus accelerates cell cycle by ubiquitination of p27 to promote hepatocellular carcinoma development

Genomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine.However,identifying a key driver gene or mutation that can be used for hepatocellular carcinoma(HCC)treatment remains difficult.Here,we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S(p.Gly57Ala and p.Lys63Asn).Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious.Further,we observed that wild-type UBE2S,especially in the nucleus,was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC.Functional assays revealed that overexpression of UBE2S promoted the proliferation,invasion,metastasis,and G1/S phase transition of HCC cells in vitro,and promoted the tumor growth significantly in vivo.Mechanistically,UBE2S interacted with TR1M28 in the nucleus,both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression.Most importantly,the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen(HTS)to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo,which may represent a promising strategy for HCC therapy.

Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication.Meplazumab is a humanized anti-CD147 IgG_(2) monoclonal antibody,which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019(COVID-19)patients.Here,we conducted a randomized,double-blinded,placebo-controlled phase 1 trial to evaluate the safety,tolerability,and pharmacokinetics of meplazumab in healthy subjects,and an open-labeled,concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients.In phase 1 study,59 subjects were enrolled and assigned to eight cohorts,and no serious treatment-emergent adverse event(TEAE)or TEAE grade≥3 was observed.The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics.No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort.The biodistribution study indicated that meplazumab reached lung tissue and maintained>14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32.In the exploratory phase 2 study,17 COVID-19 patients were enrolled,and 11 hospitalized patients were involved as concurrent control.The meplazumab treatment significantly improved the discharged(P=0.005)and case severity(P=0.021),and reduced the time to virus negative(P=0.045)in comparison to the control group.These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

CD147 contributes to SARS-CoV-2-induced pulmonary fibrosis

COVID‐19 patients can develop clinical and histopathological features associated with fibrosis,but the pathogenesis of fibrosis remains poorly understood.CD147 has been identified as a universal receptor for SARS-CoV-2 and its variants,which could initiate COVID-19-related cytokine storm.Here,we systemically analyzed lung pathogenesis in SARS-CoV-2-and its delta variant-infected humanized CD147 transgenic mice.Histopathology and Transmission Electron Microscopy revealed inflammation,fibroblast expansion and pronounced fibrotic remodeling in SARS-CoV-2-infected lungs.Consistently,RNA-sequencing identified a set of fibrosis signature genes.Furthermore,we identified CD147 as a crucial regulator for fibroblast activation induced by SARS-CoV-2.We found conditional knockout of CD147 in fibroblast suppressed activation of fibroblasts,decreasing susceptibility to bleomycin-induced pulmonary fibrosis.Meplazumab,a CD147 antibody,was able to inhibit the accumulation of activated fibroblasts and the production of ECM proteins,thus alleviating the progression of pulmonary fibrosis caused by SARS-CoV-2.In conclusion,we demonstrated that CD147 contributed to SARS-CoV-2-triggered progressive pulmonary fibrosis and identified CD147 as a potential therapeutic target for treating patients with post-COVID-19 pulmonary fibrosis.

PDGFA-associated protein 1 is a novel target of c-Myc and contributes to colorectal cancer initiation and progression

Background:The mechanism underlying colorectal cancer(CRC)initiation and progression remains elusive,and overall survival is far from satisfactory.Previous studies have shown that PDGFA-associated protein 1(PDAP1)is upregulated in several cancers including CRC.Here,we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target.Methods:Multi-omics data analysis was performed to identify potential key players in CRC initiation and progression.Immunohistochemistry(IHC)staining was applied to determine the expression pattern of PDAP1 in CRC tissues.Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models.RNA sequencing,a phosphoprotein antibody array,western blotting,histological analysis,5-bromo-2′-deoxyuridine(BrdU)incorporation assay,and interactome analysis were applied to identify the underlying mechanisms of PDAP1.A human patient-derived xenograft(PDX)model was used to assess the potential of PDAP1 as a therapeutic target.Results:PDAP1 was identified as a potential key player in CRC development using multi-omics data analysis.PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival.Further investigation showed that PDAP1 was critical for the regulation of cell proliferation,migration,invasion,and metastasis.Significantly,depletion of Pdap1in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt-induced colitis and inhibited tumor initiation and growth in colitis-associated cancers.Mechanistic studies showed that c-Myc directly transactivated PDAP1,which contributed to the high PDAP1 expression in CRC cells.PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor(EGFR)and facilitated EGFRmitogen-activated protein kinase(MAPK)signaling activation,which resulted in FOS-related antigen 1(FRA-1)expression,thereby facilitating CRC progression.Notably,silencing of PDAP1 could hinder the growth of patient-derived xenografts that sustain high PDAP1 levels.Conclusions:PDAP1 facilitates mucosal restitution and carcinogenesis in colitis-associated cancer.c-Myc-driven upregulation of PDAP1 promotes proliferation,migration,invasion,and metastasis of CRC cells via the EGFRMAPK-FRA-1 signaling axis.These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.

CD98-induced CD147 signaling stabilizes the Foxp3 protein to maintain tissue homeostasis

Regulatory T cell(Treg)stability is necessary for the proper control of immune activity and tissue homeostasis.However,it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions.Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability.Here,we demonstrate that to maintain Foxp3 protein expression,Tregs require cell-to-cell contact,which is mediated by the CD147-CD98 interaction.As Tregs are produced,CD147,which is expressed on their surface,is stimulated by CD98,which is widely expressed in the physiological environment.As a result,CD147’s intracellular domain binds to CDK2 and retains it near the membrane,leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation.In addition,the optimal distribution of Foxp3+Tregs under both pathological and physiological conditions depends on CD98 expression.Thus,our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment.More importantly,Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability,which has guiding significance for the application of Tregs in immunotherapy.

CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFβ

Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity.Here,we show that the loss of CD147 on T cells prevents thymic senescence,resulting in slowed shrinkage of the thymus with age and increased production of naive T cells.This phenotype is the result of slowing of the epithelial-mesenchymal transition(EMT)process in thymic epithelial cells(TECs),which eventually leads to reduced adipocyte accumulation.In an in vitro coculture system,we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-5mad2/FoxC2 signaling.Moreover,CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs.In the presence of TGFβ,Annexin A2 and E-cadherin colocalize on TECs.However,CD147 on T cells competitively binds to Annexin A2 on TECs,leading to the isolation of E-cadherin.Then,the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase,the phosphorylation of which was induced by TGFβ,and finally,p-E-cadherin is degraded.Thus,in the thymus,the interaction between T ceils and TECs contributes to thymic involution with age.In this study,we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.