查看更多>>摘要：The gastrointestinal tract is densely innervated by the peripheral nervous system and populated by the immune system.These two systems critically coordinate the sensations of and adaptations to dietary,microbial,and damaging stimuli from the external and internal microenvironment during tissue homeostasis and inflammation.The brain receives and integrates ascending sensory signals from the gut and transduces descending signals back to the gut via autonomic neurons.Neurons regulate intestinal immune responses through the action of local axon reflexes or through neuronal circuits via the gut-brain axis.This neuroimmune crosstalk is critical for gut homeostatic maintenance and disease resolution.In this review,we discuss the roles of distinct types of gut-innervating neurons in the modulation of intestinal mucosal immunity.We will focus on the molecular mechanisms governing how different immune cells respond to neural signals in host defense and inflammation.We also discuss the therapeutic potential of strategies targeting neuroimmune crosstalk for intestinal diseases.
查看更多>>摘要：To define the systemic neuroimmune interactions in health and disease,we recently suggested immunoception as a term that refers to the existence of bidirectional functional loops between the brain and the immune system.This concept suggests that the brain constantly monitors changes in immune activity and,in turn,can regulate the immune system to generate a physiologically synchronized response.Therefore,the brain has to represent information regarding the state of the immune system,which can occure in multiple ways.One such representation is an immunengram,a trace that is partially stored by neurons and partially by the local tissue.This review will discuss our current understanding of immunoception and immunengrams,focusing on their manifestation in a specific brain region,the insular cortex(IC).
查看更多>>摘要：Brain macrophages include microglia in the parenchyma,border-associated macrophages in the meningeal-choroid plexus-perivascular space,and monocyte-derived macrophages that infiltrate the brain under various disease conditions.The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies.As such,we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development,homeostasis and disease pathogenesis.In this review,we first outline the critical roles played by brain macrophages during development and healthy aging.We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders,autoimmune diseases,and glioma.Finally,we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.
查看更多>>摘要：Recent research in neuroimmunology has revolutionized our understanding of the intricate interactions between the immune system and the central nervous system(CNS).The CNS,an"immune-privileged organ",is now known to be intimately connected to the immune system through different cell types and cytokines.While type 2 immune responses have traditionally been associated with allergy and parasitic infections,emerging evidence suggests that these responses also play a crucial role in CNS homeostasis and disease pathogenesis.Type 2 immunity encompasses a delicate interplay among stroma,Th2 cells,innate lymphoid type 2 cells(ILC2s),mast cells,basophils,and the cytokines interleukin(IL)-4,IL-5,IL-13,IL-25,TSLP and IL-33.In this review,we discuss the beneficial and detrimental roles of type 2 immune cells and cytokines in CNS injury and homeostasis,cognition,and diseases such as tumors,Alzheimer's disease and multiple sclerosis.
查看更多>>摘要：Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe COVID-19.Here,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients(n=136)treated with different ISDs.We demonstrate that a combination of a calcineurin inhibitor(CNI),mycophenolate mofetil(MMF),and prednisone(Pred)treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response.Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection.To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients,we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor(TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta,Delta,Gamma,and Omicron variants.This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.
查看更多>>摘要：Aeroallergen sensitization,mainly mediated by lung epithelium and dendritic cells(DCs),is integral to allergic asthma pathogenesis and progression.IL-10 has a dual role in immune responses,as it inhibits myeloid cell activation but promotes B-cell responses and epithelial cell proliferation.Here,we report a proinflammatory function of B-cell-derived IL-10 modulated by Bcl-3 in allergic asthma.Specifically,Bcl-3-/-mice showed elevated IL-10 levels and were found to be highly vulnerable to allergic asthma induced by house dust mites(HDMs).IL-10 had a positive correlation with the levels of the DC chemoattractant CCL-20 in HDM-sensitized mice and in patients with asthma and induced a selective increase in CCL-20 production by mouse lung epithelial cells.Blockade of IL-10 or IL-10 receptors during sensitization dampened both HDM-induced sensitization and asthma development.IL-10 levels peaked 4 h post sensitization with HDM and IL-10 was primarily produced by B cells under Bcl-3-Blimp-1-Bcl-6 regulation.Mice lacking B-cell-derived IL-10 displayed decreased lung epithelial CCL-20 production and diminished DC recruitment to the lungs upon HDM sensitization,thereby demonstrating resistance to HDM-induced asthma.Moreover,responses to HDM stimulation in Bcl-3-/-mice lacking B-cell-derived IL-10 were comparable to those in Bcl-3+/+ mice.The results revealed an unexpected role of B-cell-derived IL-10 in promoting allergic sensitization and demonstrated that Bcl-3 prevents HDM-induced asthma by inhibiting B-cell-derived IL-10 production.Thus,targeting the Bcl-3/IL-10 axis to inhibit allergic sensitization is a promising approach for treating allergic asthma.
查看更多>>摘要：Antigen-specific T-cell recognition is restricted by Major Histocompatibility Complex(MHC)molecules,and differences between CD4 and CD8 immunogenicity in humans and animal species used in preclinical vaccine testing are yet to be fully understood.In this study,we addressed this matter by analyzing experimentally identified epitopes based on published data curated in the Immune Epitopes DataBase(IEDB)database.We first analyzed SARS-CoV-2 spike(S)and nucleoprotein(N),which are two common targets of the immune response and well studied in both human and mouse systems.We observed a weak but statistically significant correlation between human and H-2b mouse T-cell responses(CD8 S specific(r=0.206,p=1.37×10-13);CD4 S specific(r=0.118,p=2.63×10-5)and N specific(r=0.179,p=2.55×10-4)).Due to intrinsic differences in MHC molecules across species,we also investigated the association between the immunodominance of common Human Leukocyte Antigen(HLA)alleles for which HLA transgenic mice are available,namely,A*02:01,B*07:02,DRB1*01:01,and DRB1*04:01,and found higher significant correlations for both CD8 and CD4(maximum r=0.702,p=1.36×10-31 and r=0.594,p=3.04-122,respectively).Our results further indicated that some regions are commonly immunogenic between humans and mice(either H-2b or HLA transgenic)but that others are human specific.Finally,we noted a significant correlation between CD8 and CD4 S-(r=0.258,p=7.33×1021)and N-specific(r=0.369,p=2.43×1014)responses,suggesting that discrete protein subregions can be simultaneously recognized by T cells.These findings were confirmed in other viral systems,providing general guidance for the use of murine models to test T-cell immunogenicity of viral antigens destined for human use.
查看更多>>摘要：Inhibitory immune receptors set thresholds for immune cell activation,and their deficiency predisposes a person to autoimmune responses.However,the agonists of inhibitory immune receptors remain largely unknown,representing untapped sources of treatments for autoimmune diseases.Here,we show that V-set and transmembrane domain-containing 1(VSTM1)is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1(Gal1)is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production.However,in patients with systemic lupus erythematosus(SLE),circulating Gal1 is oxidized and cannot be recognized by VSTM1,leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability.Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes.Interestingly,serum levels of glutathione,an antioxidant able to convert oxidized Gal1 to its reduced form,were negatively correlated with SLE disease activity.Taken together,our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.
查看更多>>摘要：Thiostrepton(TST)is a natural antibiotic with pleiotropic properties.This study aimed to elucidate the therapeutic effect of TST on experimental colitis and identify its targets.The effect of TST on colon inflammation was evaluated in a dextran sulfate sodium(DSS)-induced colitis model and a T-cell transfer colitis model.The therapeutic targets of TST were investigated by cytokine profiling,immunophenotyping and biochemical approaches.The effect of TST on the gut microbiota and its contribution to colitis were evaluated in mice with DSS-induced colitis that were subjected to gut microbiota depletion and fecal microbiota transplantation(FMT).Alterations in the gut microbiota caused by TST were determined by 16S rDNA and metagenomic sequencing.Here,we showed that TST treatment significantly ameliorated colitis in the DSS-induced and T-cell transfer models.Specifically,TST targeted the retinoic acid-related orphan nuclear receptor RORγt to reduce the production of IL-17A by γδ T cells,type 3 innate lymphoid cells(ILC3s)and Th17 cells in mice with DSS-induced colitis.Similarly,TST selectively prevented the development of Th17 cells in the T-cell transfer colitis model and the differentiation of naïve CD4+ T cells into Th17 cells in vitro.Mechanistically,TST induced the ubiquitination and degradation of RORγt by promoting the binding of Itch to RORγt.Moreover,TST also reversed dysbiosis to control colonic inflammation.Taken together,these results from our study describe the previously unexplored role of TST in alleviating colonic inflammation by reducing IL-17A production and modulating dysbiosis,suggesting that TST is a promising candidate drug for the treatment of IBD.
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