Immunology最新文献

Natural killer (NK) cell immunosuppression represents a critical factor in patients with progressive hepatocellular carcinoma (HCC), yet its underlying characteristics at the single-cell level remain poorly defined. This study investigates the functional and metabolic alterations in NK cells associated with progressive HCC. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood samples from six treatment-naïve HCC patients, categorised into progressive and stable disease groups based on a 3-year follow-up. This was complemented by multicolor flow cytometry of peripheral blood, alongside multicolor fluorescence analyses of paired tumour and adjacent tissues. Our analyses revealed a significant reduction in NK cell proportion and a marked downregulation of immune-related genes in patients with progressive HCC. scRNA-seq further identified a distinct NK cell characterised by high expression of HAVCR2 (TIM3). Compared to TIM3^-NK cells, TIM3⁺NK cells exhibited an exhausted phenotype, evidenced by upregulated CD39 and TIGIT, impaired functional capacity (reduced CD107a and IFN-γ) and downregulated key glycolytic enzymes (HK2, ATP5a). Clinically, high TIM3 expression correlated with shorter progression-free survival and an increased risk of tumour progression. Collectively, our findings delineate a state of NK cell immunosuppression and metabolic impairment in progressive HCC, potentially driven by glycolytic reprogramming and establish TIM3 as a critical marker and potential therapeutic target.

This review provides an in-depth analysis of the complex bidirectional interaction mechanisms between tumour-associated macrophages (TAMs) and T cells in the tumour microenvironment (TME). It elaborates on how TAMs, especially M2-type TAMs, suppress the anti-tumour function of T cells and induce their exhaustion through multiple pathways, such as secreting immunosuppressive cytokines (e.g., IL-10, TGF-β), highly expressing immune checkpoint ligands (e.g., PD-L1), recruiting other immunosuppressive cells (e.g., Treg cells), depleting key metabolites (e.g., arginine), and remodelling the extracellular matrix (ECM), thereby promoting tumour immune escape and disease progression. Meanwhile, the review also explores how T cells reverse-regulate the polarization state of TAMs through the activation of the CD40-CD40L axis and the secretion of specific cytokines (e.g., IFN-γ or IL-4). Based on this, the review systematically proposes innovative immunotherapy strategies targeting this key bidirectional interaction, including blocking the recruitment of TAMs (e.g., CCL2/CCR2, CXCL12/CXCR4 inhibitors), directly eliminating TAMs (e.g., CSF1R inhibitors, bisphosphonates, trabectedin), or reprogramming them into anti-tumour M1-type (e.g., CD40 agonists, TLR agonists, CD47-SIRPα axis blockers), and emphasises the great potential of combining these TAM-targeting strategies with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies). These combined therapies aim to synergistically enhance efficacy and overcome the current challenges of drug resistance in immunotherapy, offering new hope for more durable and effective treatment for cancer patients. Additionally, the review looks forward to the application prospects of advanced cell therapies such as nanoparticle delivery systems and chimeric antigen receptor macrophages (CAR-M) in reshaping the TME and enhancing anti-tumour immune responses, providing multi-dimensional and in-depth theoretical basis and practical directions for future cancer immunotherapy.

To investigate the role of PANoptosis activation in anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (anti-MDA5+ DM). Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from 40 patients with anti-MDA5+ DM and 10 healthy controls (HCs) was performed. The PANoptosis signature score was constructed using single sample gene set enrichment analysis based on the mean enrichment scores of the pyroptosis, apoptosis and necroptosis gene sets, and the clinical associations of the PANoptosis signature score in patients with anti-MDA5+ DM were evaluated. PANoptosis markers were analysed via western blotting, and the regulatory mechanism of PANoptosis activation was studied in Jurkat cells in vitro. Transcriptomic profiling demonstrated overactivation of the PANoptosis signalling pathway in patients with anti-MDA5+ DM. The PANoptosis signature score was positively correlated with inflammatory markers, type 1 interferon (IFN) signature score, disease severity and poor prognosis in patients with anti-MDA5+ DM. Z-DNA binding protein 1 (ZBP1) was identified as a key PANoptosis-related gene in anti-MDA5+ DM. PANoptosis markers, including P-MLKL, GSDMD-N, cleaved caspase-8, cleaved caspase-3 and cleaved caspase-7, were significantly upregulated in T cells from patients with anti-MDA5+ DM. Functional assays demonstrated that IFN-β induced PANoptosis activation in T cells in vitro, which was significantly attenuated following ZBP1 knockdown. PANoptosis overactivation was associated with disease severity and prognosis in anti-MDA5+ DM. Our findings indicated that IFN-β triggered ZBP1-mediated PANoptosis in T cells, highlighting PANoptosis as a novel potential therapeutic target for anti-MDA5+ DM.

This study was a post hoc analysis of a Phase III trial (NCT04839016), which aims to investigate whether early response to vunakizumab can predict long-term efficacy in plaque psoriasis patients. A total of 461 plaque psoriasis patients receiving vunakizumab treatment were included for analysis. Early response to vunakizumab was defined by patients achieving a psoriasis area and severity index (PASI) 50 at week (W) 2. Efficacy analysis included PASI 75/90/100 and static physician's global assessment (sPGA) 0/1 response rates in both groups. Safety was analysed in both groups. At W2, 249 patients achieved an early response; 212 did not. At W12, higher proportions of patients in the early response group achieved PASI 75/90/100 and sPGA 0/1 versus the without early response group (98.4% vs. 88.2%, 88.0% vs. 66.0%, 50.2% vs. 25.0%, 84.7% vs. 64.6%, respectively; all p < 0.001). The early response group had higher proportions of patients who maintained PASI 75/90/100 and sPGA 0/1 from W12 to W52 versus the without early response group (88.8% vs. 76.4%, 74.7% vs. 54.7%, 39.4% vs. 20.8%, 68.7% vs. 54.2%, respectively; all p < 0.001). Multivariate logistic regression analysis showed that early response to vunakizumab was independently associated with PASI 100 response at W52 (odds ratio = 1.772, p = 0.027). The incidence of adverse events was similar between groups. Patients with moderate-to-severe plaque psoriasis receiving vunakizumab show a favourable clinical response, regardless of achieving early response or not. Particularly, patients with early response at Week 2 are significantly more likely to achieve better long-term treatment outcomes.

Systemic lupus erythematosus (SLE) is an autoimmune disease marked by dysregulated T cell responses and elevated pro-inflammatory cytokines such as IL-17A. Identifying reliable biomarkers could improve diagnosis and understanding of SLE pathogenesis. This study aimed to characterise CD161 and CCR6 expression on peripheral T cells in SLE and evaluate their diagnostic potential. Peripheral blood mononuclear cells were obtained from 34 new onset SLE patients, 26 primary Sjögren's syndrome (pSS) patients and 20 age- and sex-matched healthy controls. Flow cytometry profiled CD4⁺ and CD8⁺ T cells for CD161, CCR6, CXCR3 and intracellular IL-17A. Standard laboratory assays measured complete blood counts, CRP, ESR, complement, immunoglobulins and autoantibodies. Statistical analyses included Student's t-test, Mann-Whitney test, or ANOVA for group comparisons, Spearman's correlation and receiver operating characteristic (ROC) curve analysis with cut-offs determined by the Youden index. A distinct CD4⁺CD161⁺CCR6⁺ subset was present in healthy blood and showed significantly higher IL-17A than CD161⁺CCR6^- or CD161^-CCR6⁺ cells. In SLE patients, the frequency of CD4⁺CD161⁺CCR6⁺ cells was markedly increased compared to healthy controls (median 18.0% vs. 9.2%, p < 0.001) and CD4⁺CD161⁺ alone was also elevated (p < 0.05). ROC analysis distinguishing SLE from healthy controls yielded AUCs of 0.993 for CD4⁺CD161⁺, 0.774 for CD4⁺CD161⁺CCR6⁺ and 0.526 for CD4⁺CCR6⁺. Using pSS as disease controls, CD4⁺CD161⁺CCR6⁺ cells achieved an AUC of 0.868. CD161⁺CCR6⁺ CD4⁺ T cells are enriched for IL-17A and significantly elevated in early SLE, demonstrating moderate diagnostic accuracy. These findings support their potential role as novel blood biomarkers for SLE.

Type 1 diabetes (T1D) arises from T cell-mediated destruction of pancreatic β-cells. However, genetic susceptibility alone cannot account for the increasing incidence and earlier onset of T1D, suggesting a substantial contribution from environmental factors, particularly the gut microbiota. This review synthesises recent human, multiomics and experimental evidence linking gut microbiota dysbiosis and microbial metabolites to β-cell autoimmunity. We focus on two converging mechanisms: (1) metabolite-driven disruption of intestinal barrier integrity and immune regulation, and (2) molecular mimicry between microbial peptides and islet autoantigens that activate autoreactive T cells. Across human cohorts and animal models, T1D-associated dysbiosis features reduced short-chain fatty acid (SCFA)-producing bacteria (e.g., Faecalibacterium, Roseburia) and increased pro-inflammatory taxa (e.g., Bacteroides, Streptococcus spp.). SCFA deficiency compromises Treg induction and gut barrier stability, facilitating antigen translocation. Several gut-derived peptides, such as the Parabacteroides distasonis hprt4-18 peptide, share sequence homology with insulin and other islet antigens, activate insulin-reactive T cells and accelerate diabetes in NOD mice, supporting a role for molecular mimicry. Interventional approaches including FMT, probiotics and prebiotics show promise but remain heterogeneous; their efficacy is highly strain-, timing- and context-dependent and translation from animal studies to humans is still limited. Therapeutically targeting the gut-islet axis, through modulation of microbiota, microbial metabolites or cross-reactive antigens, offers potential for disease prevention or adjunctive treatment. We highlight emerging biomarkers, including MAIT-cell phenotypes, antimicrobial peptide reactivity and microbiome-derived functional signatures, and emphasise the need for stratified clinical trial designs based on age, genotype and baseline microbiota composition to address current variability. The microbiota-metabolite-molecular mimicry axis provides a coherent mechanistic framework linking gut dysbiosis to T1D pathogenesis. Advancing these insights into clinical application will require rigorous, genotype-stratified human studies and standardised, transparent methodological approaches.

Regulatory T cells (Tregs) display metabolic fitness to adopt tumour microenvironment (TME), characterized by hypoxia, acidity and metabolic depletion/competition, in order to impair anti-tumour immunity and allow metastasis. Tregs and other TME immune cells interact metabolically, with glycolysis supporting proliferation of Tregs along with cancer cells and CD8⁺ T cells and a basal oxidative phosphorylation (OXPHOS) promoting Treg and CD8⁺ T cell activity. Lactate is a glycolysis byproduct that its accumulation creates acidosis within TME, and its uptake provides a fuel source for Treg activity and fosters their persistence in the hypoxic TME. Itaconate and hypoxic TME increase succinate accumulation, but they take complex roles on Tregs and T cells. Hypoxia and hypoxia inducible factor-1 (HIF-1) activity induce lactate release and Treg recruitment/accumulation via stimulating glycolysis path and extracellular adenosine aggregation. Knockout of HIF-1α although reduces lactate, it secondarily induces OXPHOS to fulfil Treg immunosuppressive function. FOXP3 is stabilized by mitochondrial transcription factor A (Tfam) and induces Treg CD36 and OXPHOS, which can be disturbed by nucleus accumbens-associated protein 1 (NAC1). Liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) although induce FOXP3 stability and OXPHOS in Tregs, their activities downregulate programmed death-1 (PD-1) in such cells. OXPHOS augmentation (by α-ketoglutarate [αKG]) or suppression (by metformin) disrupt Treg metabolism. Finally, indoleamine 2,3-dioxygenase (IDO) seems to affect Tregs and can be a promising target in advanced immunotherapy naïve cancer patients. The focus of this review is to describe Treg metabolic regulators/connectome and opportunities they bring about in cancer therapy.

Ecotin, a metabolite secreted by gut microbiota, improved the survival of virus-infected mice when administered via standalone injection. Vaccination of mice with a formulation of recombinant Ecotin and RBD-Fc antigen elicited an earlier production of IgG antibodies, accompanied by a marked increase in the number of CD3⁺ T cells in mouse lung tissues.

Metabolic reprogramming induced by viral infections plays a key role in shaping the efficacy and durability of the host's adaptive immune response. Notably, metabolic reprogramming not only directly governs the differentiation fates of functional subgroups, such as Th1, Th2, Th17, Treg and cytotoxic T cells, but also contributes to supportive immune responses and T-cell exhaustion mediated by metabolic disorders in the context of acute and chronic infections, respectively. Moreover, the metabolic reprogramming of B cells precisely regulates their germinal centre response, plasma cell differentiation and antibody production, thereby modulating the intensity and quality of humoral immunity. Beyond these direct effects, viruses indirectly impair the functionality of T and B cells by altering the metabolic status of innate immune cells such as dendritic cells and macrophages. This review summarises the recent advances of regulatory mechanisms regarding metabolic characteristics of T cells and B cells at various statuses, including rest, activation, differentiation and memory, and discusses immune intervention strategies targeting glycolysis, glutamine and lipid metabolism, and outlines future research directions and clinical translation potential of metabolic reprogramming. A comprehensive understanding of virus-mediated metabolic reprogramming will provide an important theoretical basis for the development of new antiviral therapies and immunotherapy strategies.

Follicular helper T (Tfh), B and regulatory T (Treg) cells are involved in the pathogenesis of chronic rejection (CR) after transplantation. Dihydroartemisinin (DHA) is an antimalarial drug with anti-inflammatory activity; however, the effects and mechanisms of DHA on Tfh, B and Treg cells have not been comprehensively elucidated. The aim of this study was to investigate the effect of DHA on Tfh, B and Treg cells and its preventive effect on CR. In vitro assays demonstrated that DHA not only blocks the induction of Tfh cells and alleviates their supportive effect on B cell differentiation but also directly suppresses B cell activation, differentiation and antibody production. Additionally, DHA promotes the induction of Treg cells and enhances their stability in an inflammatory environment. In vivo studies showed that DHA effectively alleviated CR by suppressing neointimal hyperplasia, myocardial injury and interstitial fibrosis and reducing inflammatory cell infiltration and C4d deposition in allografts. Moreover, DHA decreased the levels of Tfh, germinal centre Tfh, B, germinal centre B, IgG-producing and plasma cells in recipients but increased Treg cell levels in recipients and allografts. Mechanistically, we confirmed that DHA inhibits Tfh cells by blocking IL-2-inducible T cell kinase signalling, suppresses B cells by blocking Bruton's tyrosine kinase signalling, and enhances Treg cells by blocking mTOR signalling while promoting STAT5 signalling. In conclusion, our results verified that DHA inhibits Tfh and B cells and enhances Treg cells to attenuate CR in mice, highlighting its potential applicability in the development of robust treatment options.