参考文献

Solid tumor malignancy (STM) patients experience increased risk of breakthrough SARS-CoV-2 infection owing to reduced COVID-19 vaccine immunogenicity. However,the underlying immunological causes of impaired neutralization remain poorly characterized. Furthermore,non-neutralizing antibody functions can contribute to reduced disease severity but remain understudied within high-risk populations. We dissected polyfunctional antibody responses in STM patients and age-matched controls who received adenoviral vector- or mRNA-based COVID-19 vaccine regimens. Elevated inflammatory biomarkers,including agalactosylated IgG,interleukin (IL)-6,IL-18,and an expanded population of CD11c−CD21− double negative 3 (DN3) B cells were observed in STM patients and were associated with impaired neutralization. In contrast,mRNA vaccination induced Fc effector functions that were comparable in patients and controls and were cross-reactive against SARS-CoV-2 variants. These data highlight the resilience of Fc functional antibodies and identify systemic inflammatory biomarkers that may underpin impaired neutralizing antibody responses,suggesting potential avenues for immunomodulation via rational vaccine design. View Publication

Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS. However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood. To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses. Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4 (RBP4),the carrier of retinol (Vitamin A). We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines. Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production. High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1. Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads. As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure. Subject terms: Preclinical research,Infectious diseases View Publication

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder,with no effective treatment currently available. Recently,non-pharmacological therapy,especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer’s disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However,whether EF is beneficial in AD neuropathology remains unknown. In this study,we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies,suppressed microglial activation,neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover,EF treatment induced cell-specific responses in neural cells,with neurons being more susceptible,followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons,inflammatory response and complement signaling in microglia,and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-025-01859-8. View Publication

BackgroundAutoantibodies against envelope (Env) protein encoded by human endogenous retrovirus group K (HERV-K) are prevalent in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE),but it remains unclear which proviruses are responsible for this autoantigen. It also remains poorly understood how the transcription of HERV-K loci is regulated in cells that can produce Env.ResultsWe aligned our neutrophil RNA sequencing data to the new telomere-to-telomere reference genome and found uniquely mapping transcripts from HERV-K101,K102,K104,K108,K109,K117 and ERVK5,of which only K102,K108,and K109 encode an intact Env. Expression of K102 and K108 were higher in SLE than in healthy donors or RA (padj < 0.05). Transcripts from these proviruses increased in response to interferon-α in monocytes and neutrophils from RA patients and healthy donors,but not in SLE,presumably because they have chronically elevated type I interferons in vivo. Indeed,HERV-K expression was significantly higher in SLE patients with high type I interferon gene signature. Tumor necrosis factor-α and other cytokines and TLR ligands also induced HERV-K102 and K108 transcripts. Interferon-α also increased detectable Env protein in monocytes,macrophages,and neutrophils from RA patients. Among the genes for epigenetic silencers of HERV-K,only TRIM28 was significantly decreased in SLE patients with high interferons (padj = 0.00024).ConclusionsOur data establish a role for interferons in maintaining increased HERV-K expression in SLE and suggest that interferons or other cytokines can upregulate HERV-K to similar levels in RA. A transient increase may also accompany normal immune responses,suggesting that endogenous retroviruses may have been co-opted for efficient immune responses.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13100-025-00371-y. Key points Expression of HERV-K provirus is elevated in neutrophils from IFN-positive SLETNFα,IFN,and other cytokines induce similar HERV-K expression also in RAHealthy donor myeloid cells respond only transiently with HERV-K transcription Supplementary InformationThe online version contains supplementary material available at 10.1186/s13100-025-00371-y. View Publication

T cell dysfunction is a pivotal driving factor in autoimmune diseases,yet its underlying regulatory mechanisms remain incompletely understood. The role of long non-coding RNAs (lncRNAs) in immune regulation has gradually been recognized,although their functional mechanisms in T cells remain elusive. This study focuses on lncBADR (LncRNA Branched-chain Amino acids Degradation Regulator),elucidating its mechanism by which it regulates branched-chain amino acids (BCAAs) metabolism to influence T cell effector functions. Mice with specific knockout of lncBADR (T celllncBADR−/−) exhibited markedly ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. Mechanistic investigations revealed that lncBADR inhibits BCAAs degradation by binding to the enzymes Mccc1 and Pcca,leading to the accumulation of BCAAs within T-cells. This,in turn,activates the mTOR-Stat1 signaling pathway,promoting IFN-γ secretion and exacerbating EAE pathology. In contrast,knockout of lncBADR restored BCAAs degradation,significantly reducing IFN-γ secretion in T cells and suppressing their pathogenic functions. Further studies demonstrated that high-BCAAs feeding partially reversed the protective effects of lncBADR knockout,indicating that lncBADR plays a crucial role in autoimmune inflammation by regulating BCAAs metabolism. This study offers new insights into targeting lncBADR or modulating BCAAs metabolism as potential therapeutic strategies for autoimmune diseases.Graphical Abstract Supplementary InformationThe online version contains supplementary material available at 10.1186/s12974-025-03538-9. View Publication

Primary human endothelial cells represent an essential tool to model endothelial dysfunction and to screen interventions for its treatment. Here,we developed a protocol for the synchronous isolation of primary human saphenous vein endothelial cells (HSaVEC),human internal thoracic artery endothelial cells (HITAEC),and human microvascular endothelial cells (HMVEC) from SV and ITA utilized as conduits during coronary artery bypass graft surgery and from subcutaneous adipose tissue excised while providing an access to the heart. Treatment by collagenase type IV and magnetic separation with anti-CD31-antibody-coated beads ensured relatively high efficiency of the isolation (≈60% for HSaVEC,≈50% for HITAEC,and ≈20% for HMVEC) and high purity (≥99%) of isolated ECs within ≈2 weeks (HSaVEC),≈2–3 weeks (HITAEC),and ≈3–4 weeks (HMVEC). A colorimetric assay of cell viability and proliferation,as well as real-time bioimpedance monitoring using the xCELLigence instrument,demonstrated high proliferative activity in HSaVEC,HITAEC,and HMVEC,whilst the in vitro tube formation assay indicated their angiogenic potential. The isolation of HSaVEC,HITAEC,and HMVEC from patients undergoing coronary artery bypass graft surgery is a promising option to investigate endothelial heterogeneity,to interrogate endothelial responses to various stresses,and to pinpoint the optimal approaches for restoring endothelial homeostasis,thereby reproducing them within the bedside-to-bench-to-bedside concept. View Publication

BackgroundHigh densities of tertiary lymphoid structures (TLSs) are associated with improved clinical outcomes in various malignancies,including human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). However,the role of TLSs in shaping antitumor immunity in HPV-induced cervical cancer (CESC) remains unclear. Therefore,we analyzed the density,composition,and prognostic impact of TLSs in patients with CESC as well as patients with HNSCC.MethodsMultiplex immunofluorescence,immunohistochemistry,and spatial transcriptomics were used to analyze TLS density and composition in HNSCC and CESC tissue sections with respect to patient prognosis. The spatial approach was supplemented by flow cytometry-based analysis of the polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype in freshly resected primary tumor tissues.ResultsAlthough both indications were associated with HPV infection,we confirmed a positive correlation between TLS density and improved overall survival only in patients with HNSCC. The TLS composition differed markedly between HNSCC and CESC samples,with a shift toward high regulatory T cell (Treg) and PMN-MDSC abundance in CESC samples. The highest Treg and PMN-MDSC levels were observed in patients with CESC who died of the disease. CESC-infiltrating PMN-MDSCs showed high arginase 1 expression,which correlated with diminished T-cell receptor (TCR)ζ chain expression in CESC-infiltrating T cells. Additionally,the high number of PMN-MDSCs in TLSs was associated with the absence of HPV-specific T cells in CESC.ConclusionsUnlike in HNSCC,the composition of TLSs,rather than their quantity,was associated with the overall survival of patients with CESC. High numbers of Tregs and PMN-MDSCs infiltrating immature TLSs prevail in patients with CESC who succumbed to the disease and seem to affect tumor-specific immune responses. View Publication

Cannabinoid receptor 1 (CB1) has been implicated in multiple inflammatory diseases by regulating pro-inflammatory mediators or altering immune cell polarization. However,the expression and direct functional role of CB1 in T cells remain largely unexplored. Here,we demonstrate that primary murine T cells express CB1 and that its novel agonist,BI-5756,directly increases the frequencies of regulatory T cells (Tregs) in primary murine pan T cells after activation. In addition,BI-5756 exhibits an in vivo protective effect against graft-versus-host disease (GvHD),an allogeneic T cell-mediated inflammatory complication after allogeneic hematopoietic cell transplantation (allo-HCT),resulting in an improved overall survival with enhanced platelet recovery and reconstitution of bone marrow-derived B and T cells. BI-5756 also directly suppresses tumor cell growth and upregulates MHC I,MHC II,and CD80 on tumor cells,which may subsequently enhance T cell-mediated anti-tumor responses in mixed lymphocyte reaction with A20 cells. The ability of BI-5756 to increase Tregs was significantly abrogated by rimonabant,a potent and selective CB1 antagonist,suggesting that the immunomodulatory effect of BI-5756 is mediated via CB1. In summary,BI-5756,a potent CB1 agonist,increases Tregs while preserving anti-tumor responses in vitro and effectively reduces GvHD in vivo. View Publication

Purpose: To investigate the therapeutic potential of inducible pluripotent stem cell (hiPSC)-based vascular repair,we evaluated two vascular reparative cell populations,CD34+ cells derived from hiPSC (hiPSC-CD34+) and endothelial colony forming cells (ECFCs) derived from hiPSC (iPS-ECFCs),alone and in combination,in a type 2 diabetic (db/db) mouse model of DR. Methods: hiPSC-CD34+ cells (1 × 104) or iPSC- ECFCs (1 × 105) alone or in combination (1.1 × 105) were injected into the vitreous of immunosuppressed db/db mice with six months of established diabetes. One month post-injection,mice underwent electroretinography (ERG) and optical coherence tomography (OCT) to evaluate functional and structural retinal recovery with iPSC administration. Immunohistochemistry (IHC) was used to assess recruitment and incorporation of cells into the retinal vasculature. Retinas from the experimental groups were analyzed using Functional Proteomics via Reverse Phase Protein Array (RPPA). Results: Functional assessment via ERG demonstrated significant improvements in retinal response in the diabetic cohorts treated with either hiPSC-derived CD34+ cells or hiPSC-ECFCs. Retinal thickness,assessed by OCT,was restored to near-nondiabetic levels in mice treated with hiPSC-CD34+ cells alone and the combination group,whereas hiPSC-ECFCs alone did not significantly affect retinal thickness. One month following intravitreal injection,hiPSC-CD34+ cells were localized to perivascular regions,whereas hiPSC-ECFCs were observed to integrate directly into the retinal vasculature. RPPA analysis revealed interaction-significant changes,and this was interpreted as a combination-specific,non-additive host responses (m6A,PI3K–AKT–mTOR,glycolysis,endothelial junction pathways). Conclusions: The studies support that injection of hiPSC-CD34+ cells and hiPSC-ECFCs,both individually and in combination,showed benefit; however,iPSC combination-specific effects were identified by measurement of retinal thickness and by RPPA. View Publication

Retinoic acid (RA) plays a key role in mucosal immune regulation and tolerance,with implications for inflammatory bowel disease (IBD). However,its effects have not been extensively studied in humanized in vitro models that recapitulate epithelial–immune interactions. We established a 3D in vitro small intestinal model composed of three epithelial cell types,naïve CD4+ T cells,and monocyte/dendritic cell (M/DC) precursors derived from CD34+ umbilical cord blood hematopoietic stem/progenitor cells. The epithelial microenvironment strongly suppressed monocyte/DC differentiation and T cell activation,indicating a regulatory role of epithelial-derived signals. Retinoic acid (RA) priming of M/DC precursors induced CD103+CD11b+Sirp1α− regulatory DCs and promoted a shift from naive to memory-type T cells. Upon addition of pro-inflammatory cytokines (TNF-α,IFN-γ,IL-1β),the model mimicked an inflamed intestinal state,resulting in CD14+CD16+ inflammatory monocytes and increased T cell activation (CD25+CD69+). RA-primed DCs modestly counterbalanced T cell activation and IBD-like responses,even under inflammatory conditions. Flow cytometry and clustering analysis revealed distinct immune cell phenotypes depending on RA exposure and cytokine context. This model provides a reproducible and physiologically relevant human system to study RA-mediated immune programming in the intestinal mucosa and may support the development of novel therapeutic strategies for IBD and related inflammatory conditions. Statistical differences were evaluated using ANOVA with Tukey’s post-hoc test (n = 4; p < 0.05). View Publication