查看更多>>摘要：To improve the efficacy of lenvatinib in combination with programmed death-1(PD-1)blockade therapy for hepatocellular carcinoma(HCC),we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade,thus impeding HCC progression.After analysis of the CRISPR‒Cas9 screen,phosphatidylinositol-glycan biosynthesis class L(PIGL)ranked first in the positive selection list.PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment(TME)in vivo to support tumor cell survival.Specifically,nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20,which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells.PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importin α/β1,thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20.Clinically,elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8+T-cell enrichment in tumors.Clinically,our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.
查看更多>>摘要：Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus(SLE).However,both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis(LN)remain largely unclear.Here,we report a pathogenic role of anti-phosphatidylserine(PS)autoantibodies in the development of LN.Elevated serum PS-specific IgG levels were measured in model mice and SLE patients,especially in those with LN.PS-specific IgG accumulation was found in the kidney biopsies of LN patients.Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice.ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients.Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice,whereas depletion of B1a cells attenuated lupus progression.In culture,PS-specific B1a cells were significantly expanded upon treatment with chromatin components,while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells.Thus,our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development.Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.
查看更多>>摘要：Cytomegalovirus(CMV)reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation(allo-HSCT).Early natural killer(NK)cell reconstitution may protect against the development of human CMV(HCMV)infection post-HSCT.Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells.Nevertheless,whether expanded NK cells have stronger anti-HCMV function is unknown.Herein,we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells.Expanded NK cells showed higher expression of activating receptors,chemokine receptors and adhesion molecules;stronger cytotoxicity against HCMV-infected fibroblasts;and better inhibition of HCMV propagation in vitro than primary NK cells.In HCMV-infected humanized mice,expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion.A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection(HR=0.54,95%CI=0.32-0.93,p=0.042)and refractory HCMV infection(HR=0.34,95%CI=0.18-0.65,p=0.009)than controls and better NK cell reconstitution on day 30 post NK cell infusion.In conclusion,expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.
查看更多>>摘要：As one of the main tumor-infiltrating immune cell types,tumor-associated macrophages(TAMs)determine the efficacy of immunotherapy.However,limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy.In this study,we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models.CD146 expression in TAMs was negatively controlled by STAT3 signaling.Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling.Interestingly,CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment,partially by inhibiting transmembrane protein 176B(TMEM176B),an immunoregulatory cation channel.Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs.These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.
查看更多>>摘要：The interaction between the gastric epithelium and immune cells plays key roles in H.pylori-associated pathology.Here,we demonstrate a procolonization and proinflammatory role of tubulointerstitial nephritis antigen-like 1(TINAGL1),a newly discovered matricellular protein,in H.pylori infection.Increased TINAGL1 production by gastric epithelial cells(GECs)in the infected gastric mucosa was synergistically induced by H.pylori and IL-1β via the ERK-SP1 pathway in a cagA-dependent manner.Elevated human gastric TINAGL1 correlated with H.pylori colonization and the severity of gastritis,and mouse TINAGL1 derived from non-bone marrow-derived cells promoted bacterial colonization and inflammation.Importantly,H.pylori colonization and inflammation were attenuated in Tinagl1-/-and Tinagl1ΔGEC mice and were increased in mice injected with mouse TINAGL1.Mechanistically,TINAGL1 suppressed CCL21 expression and promoted CCL2 production in GECs by directly binding to integrin α5β1 to inhibit ERK and activate the NF-κB pathway,respectively,which not only led to decreased gastric influx of moDCs via CCL21-CCR7-dependent migration and,as a direct consequence,reduced the bacterial clearance capacity of the H.pylori-specific Th1 response,thereby promoting H.pylori colonization,but also resulted in increased gastric influx of Ly6Chigh monocytes via CCL2-CCR2-dependent migration.In turn,TINAGL1 induced the production of the proinflammatory protein S100A11 by Ly6Chigh monocytes,promoting H.pylori-associated gastritis.In summary,we identified a model in which TINAGL1 collectively ensures H.pylori persistence and promotes gastritis.
查看更多>>摘要：Neutrophil extracellular traps(NETs)participate in the rapid inhibition and clearance of pathogens during infection;however,the molecular regulation of NET formation remains poorly understood.In the current study,we found that inhibition of the wild-type p53-induced phosphatase 1(Wip1)significantly suppressed the activity of Staphylococcus aureus(S.aureus)and accelerated abscess healing in S.aureus-induced abscess model mice by enhancing NET formation.A Wip1 inhibitor significantly enhanced NET formation in mouse and human neutrophils in vitro.High-resolution mass spectrometry and biochemical assays demonstrated that Coro1a is a substrate of Wip1.Further experiments also revealed that Wip1 preferentially and directly interacts with phosphorylated Coro1a than compared to unphosphorylated inactivated Coro1a.The phosphorylated Ser426 site of Coro1a and the 28-90 aa domain of Wip1 are essential for the direct interaction of Coro1a and Wip1 and for Wip1 dephosphorylation of p-Coro1a Ser426.Wip1 deletion or inhibition in neutrophils significantly upregulated the phosphorylation of Coro1a-Ser426,which activated phospholipase C and subsequently the calcium pathway,the latter of which promoted NET formation after infection or lipopolysaccharide stimulation.This study revealed Coro1a to be a novel substrate of Wip1 and showed that Wip1 is a negative regulator of NET formation during infection.These results support the potential application of Wip1 inhibitors to treat bacterial infections.
Manuel M.VicenteInês Alves?ngela FernandesAna M.Dias...
955-968页
查看更多>>摘要：T-cell development ensures the formation of diverse repertoires of T-cell receptors(TCRs)that recognize a variety of antigens.Glycosylation is a major posttranslational modification present in virtually all cells,including T-lymphocytes,that regulates activity/functions.Although these structures are known to be involved in TCR-selection in DP thymocytes,it is unclear how glycans regulate other thymic development processes and how they influence susceptibility to disease.Here,we discovered stage-specific glycome compositions during T-cell development in human and murine thymocytes,as well as dynamic alterations.After restricting the N-glycosylation profile of thymocytes to high-mannose structures,using specific glycoengineered mice(Rag1CreMgat1fl/fl),we showed remarkable defects in key developmental checkpoints,including ß-selection,regulatory T-cell generation and γδT-cell development,associated with increased susceptibility to colon and kidney inflammation and infection.We further demonstrated that a single N-glycan antenna(modeled in Rag1CreMgat2fl/fl mice)is the sine-qua-non condition to ensure normal development.In conclusion,we revealed that mannosylated thymocytes lead to a dysregulation in T-cell development that is associated with inflammation susceptibility.
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