查看更多>>摘要：The immune system is coordinated by an intricate network of stimulatory and inhibitory circuits that regulate host responses against endogenous and exogenous insults.Disruption of these safeguard and homeostatic mechanisms can lead to unpredictable inflammatory and autoimmune responses,whereas deficiency of immune stimulatory pathways may orchestrate immunosuppressive programs that contribute to perpetuate chronic infections,but also influence cancer development and progression.Glycans have emerged as essential components of homeostatic circuits,acting as fine-tuners of immunological responses and potential molecular targets for manipulation of immune tolerance and activation in a wide range of pathologic settings.Cell surface glycans,present in cells,tissues and the extracellular matrix,have been proposed to serve as"self-associated molecular patterns"that store structurally relevant biological data.The responsibility of deciphering this information relies on different families of glycan-binding proteins(including galectins,siglecs and C-type lectins)which,upon recognition of specific carbohydrate structures,can recalibrate the magnitude,nature and fate of immune responses.This process is tightly regulated by the diversity of glycan structures and the establishment of multivalent interactions on cell surface receptors and the extracellular matrix.Here we review the spatiotemporal regulation of selected glycan-modifying processes including mannosylation,complex N-glycan branching,core 2 O-glycan elongation,LacNAc extension,as well as terminal sialylation and fucosylation.Moreover,we illustrate examples that highlight the contribution of these processes to the control of immune responses and their integration with canonical tolerogenic pathways.Finally,we discuss the power of glycans and glycan-binding proteins as a source of immunomodulatory signals that could be leveraged for the treatment of autoimmune inflammation and chronic infection.
查看更多>>摘要：SATB1(Special A-T rich Binding protein 1)is a cell type-specific factor that regulates the genetic network in developing T cells and neurons.In T cells,SATB1 is required for lineage commitment,VDJ recombination,development and maturation.Considering that its expression varies during B-cell differentiation,the involvement of SATB1 needs to be clarified in this lineage.Using a KO mouse model in which SATB1 was deleted from the pro-B-cell stage,we examined the consequences of SATB1 deletion in naive and activated B-cell subsets.Our model indicates first,unlike its essential function in T cells,that SATB1 is dispensable for B-cell development and the establishment of a broad IgH repertoire.Second,we show that SATB1 exhibits an ambivalent function in mature B cells,acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells,respectively.Third,our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response,in which this factor limits somatic hypermutation of Ig genes.
查看更多>>摘要：Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors.Numerous studies have shown that glycogen synthase kinase 3(GSK3)controls the function and development of immune cells,but whether GSK3 affects CD8+T cells is not clearly elucidated.Here,we demonstrate that mice with deletion of Gsk3α and Gsk3β in activated CD8+T cells(DKO)exhibited decreased CTL differentiation and effector function during acute and chronic viral infection.In addition,DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+T cells.Strikingly,anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice.Mechanistically,GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT,thereby in turn dampening NFAT-mediated exhaustion-related gene expression,including TOX/TOX2 and PD-1.Thus,we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.
Abrar Ul Haq KhanAlaa Kassim AliBryan MarrDonghyeon Jo...
1140-1155页
查看更多>>摘要：Natural killer(NK)cells are predominant innate lymphocytes that initiate the early immune response during infection.NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection.Tumor necrosis factor-alpha(TNFα)is a well-known inflammatory cytokine that enhances NK cell function;however,the mechanism underlying NK cell proliferation in response to TNFα is not well established.Here,we demonstrated that upon infection/inflammation,NK cells upregulate the expression of TNF receptor 2(TNFR2),which is associated with increased proliferation,metabolic activity,and effector function.Notably,IL-18 can induce TNFR2 expression in NK cells,augmenting their sensitivity toward TNFα.Mechanistically,TNFα-TNFR2 signaling upregulates the expression of CD25(IL-2Rα)and nutrient transporters in NK cells,leading to a metabolic switch toward aerobic glycolysis.Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice.Accordingly,our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis,leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo.Collectively,our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation,glycolysis,and effector function.
查看更多>>摘要：The gut microbiome is recognized as a key modulator of sepsis development.However,the contribution of the gut mycobiome to sepsis development is still not fully understood.Here,we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis,and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture(CLP)-challenged mice and Escherichia coli-challenged pigs.Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate(PPA)enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis.Mechanistically,PPA directly binds to sirtuin 2(SIRT2)and increases reactive oxygen species(ROS)production for eventual bacterial clearance.Importantly,PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients.Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.
查看更多>>摘要：Mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders.This capacity is not innate but is activated or'licensed'by inflammatory cytokines.The licensing mechanism remains unclear.Here,we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity.In response to stimulation by inflammatory cytokines,MSCs exhibited a dramatic increase in the consumption of glucose,which was accompanied by an enhanced use of nicotinamide adenine dinucleotide(NAD+)and increased expression of nicotinamide phosphoribosyltransferase(NAMPT),a central enzyme in the salvage pathway for NAD+production.When NAD+synthesis was blocked by inhibiting or depleting NAMPT,the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated.Consequently,when NAD+metabolism in MSCs was perturbed,their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury.Further analysis revealed that NAMPT-driven production of NAD+was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs.Furthermore,the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle,which led to hypoxia-inducible factor 1α(HIF-1α)stabilization and subsequently increased the transcription of key glycolytic genes,thereby persistently maintaining glycolytic flux.This study demonstrated that unlike its proinflammatory role in immune cells,NAD+metabolism governs the anti-inflammatory function of MSCs during inflammation.
查看更多>>摘要：The adaptor molecule MAVS forms prion-like aggregates to govern the RIG-I-like receptor(RLR)signaling cascade.Lys63(K63)-linked polyubiquitination is critical for MAVS aggregation,yet the underlying mechanism and the corresponding E3 ligases and deubiquitinating enzymes(DUBs)remain elusive.Here,we found that the K63-linked polyubiquitin chains loaded on MAVS can be directly recognized by RIG-I to initiate RIG-I-mediated MAVS aggregation with the prerequisite of the CARDRIG-I-CARDMAVS interaction.Interestingly,many K63-linked polyubiquitin chains attach to MAVS via an unanchored linkage.We identified Ube2N as a major ubiquitin-conjugating enzyme for MAVS and revealed that Ube2N cooperates with the E3 ligase Riplet and TRIM31 to promote the unanchored K63-linked polyubiquitination of MAVS.In addition,we identified USP10 as a direct DUB that removes unanchored K63-linked polyubiquitin chains from MAVS.Consistently,USP10 attenuates RIG-I-mediated MAVS aggregation and the production of type I interferon.Mice with a deficiency in USP10 show more potent resistance to RNA virus infection.Our work proposes a previously unknown mechanism for the activation of the RLR signaling cascade triggered by MAVS-attached unanchored K63-linked polyubiquitin chains and establishes the DUB USP10 and the E2:E3 pair Ube2N-Riplet/TRIM31 as a specific regulatory system for the unanchored K63-linked ubiquitination and aggregation of MAVS upon viral infection.
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