Frontiers in Immunology最新文献

Background: Tryptophan (TRP) metabolism via the kynurenine (KYN) pathway links immune function, energy metabolism, and redox homeostasis. Dysregulation of this pathway has been implicated in inflammatory conditions and heart failure. Here, we investigated the acute effects of exercise on TRP-KYN metabolism and its relationship with natural killer (NK) cell function in controls and patients with heart failure with reduced ejection fraction (HFrEF).

Methods: Control (n=13) and HFrEF (n=16) groups had comparable composition regarding age and sex. Participants were investigated at baseline, immediately after a maximal symptom-limited cardiopulmonary exercise test (CPET), and after 2 hours of resting. Blood samples were obtained at all time points to assess NK cell counts and phenotypic parameters by flow cytometry, as well as tryptophan metabolites and protein secretome by mass spectrometry and targeted proteomics, respectively. NK cells and non-NK cells from blood of healthy donors were stimulated ex vivo prior to flow cytometry-based measurement, indoleamine 2,3-dioxygenase (IDO) mRNA expression analysis and mass spectrometry-based tryptophan metabolite analysis.

Results: Plasma TRP levels decreased post-exercise in both study groups, with increased metabolism down the KYN route, albeit only in HFrEF patients, a significant accumulation of quinolinate (QUIN) was seen. Increases in plasma KYN-to-TRP ratios correlated with more circulating NK cell counts and IL-12p70 levels mainly in the HFrEF group. Ex vivo, IL-12 exposure of human total primary NK cells increased representation of the CD56-bright subset, IDO mRNA expression, and TRP-to-KYN conversion, resulting in net KYN accumulation and elevated QUIN production. In non-NK cells, IFN-γ exposure similarly promoted TRP-to-KYN flux and QUIN formation.

Conclusion: Collectively, our observations confirm earlier descriptive reports of exercise-induced upregulation of KYN production by NK cells and add mechanistic evidence that IL-12 induces a phenotype shift in NK cells, which is accompanied by accelerated TRP metabolism into KYN. Our data point to a concerted interaction between leukocyte subsets upon acute exercise, via the release of IL-12, with potential implications for differential energy metabolism and immune regulation in HFrEF.

The accumulation of lactate in the tumor microenvironment (TME), driven by the Warburg effect, is closely associated with immunosuppression. Lactate can contribute to this process through lysine lactylation, a novel post-translational modification. We propose a conceptual framework, the "Lactylation-immunosuppression network," that links tumor metabolic reprogramming to immune cell signaling and gene expression. This network highlights a metabolic-epigenetic axis linking lactylation to immunosuppression via a synergistic dual mechanism: long-term epigenetic programming via histone lactylation establishes a stable immunosuppressive transcriptome, while rapid, dynamic non-histone lactylation directly modulates protein activity and stability, thereby potentiating function. This review summarizes how lactylation may undermine anti-tumor immunity by remodeling myeloid and T cell compartments, fortifying immune checkpoint barriers, and creating self-reinforcing metabolic feedback loops. By elucidating this mechanism, we highlight novel therapeutic targets, propose a "kinetic threshold" model to resolve the paradoxical role of lactate, and provide a unified conceptual framework for developing next-generation immunotherapies and guiding future mechanistic studies.

Introduction: Coronaviruses frequently undergo genomic mutation and recombination in nature. Through cross-species infection and sporadic spillover events, novel coronaviruses may periodically emerge in humans. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 all cause severe, predominantly respiratory diseases with moderate to high pathogenicity, posing a substantial threat to public health. To prepare for potential future coronavirus outbreaks, there is a need for universal vaccines capable of eliciting broad-spectrum humoral and cellular immunity.

Methods: In this study, we constructed DNA- and replicating Vaccinia virus TianTan (VTT)-vectored monovalent and trivalent vaccines, using the spike (S) proteins of the aforementioned wild-type viruses as immunogens in a heterologous DNA-prime/VTT-boost regimen.

Results: Compared with monovalent vaccines, the trivalent candidate induced robust, broad-spectrum humoral and cellular immune responses against the S proteins of SARS-CoV-1, MERS-CoV, and SARS-CoV-2 in mice. Notably, it also conferred protection against challenge with the SARS-CoV-2 XBB variant.

Discussion: These findings offer important insights for developing practical multivalent coronavirus vaccines that could help mitigate transmission and mortality early in future coronavirus outbreaks. Such an initial countermeasure could buy critical time for the development of variant-specific vaccines and further inform the design of universal coronavirus vaccines.

Immunotherapies revolutionized cancer treatment, yet their efficacy remains constrained by the tumor's immunosuppressive microenvironment. Here, we evaluated whether combining CD39 blockade with other modalities of immunotherapy such as IL-2/anti-IL-2 complexes (IL-2cx) administration could further enhance T cell-mediated antitumor responses and improve tumor control. We demonstrated that CD39 deficiency in MC38 tumor-bearing CD39KO (Entpd1 null) mice decreases tumor growth. This better tumor growth control was associated with increased infiltration of PD-1^High CD8⁺ T cells, expressing elevated levels of exhaustion markers and transcription factors such as TOX. This PD-1^High CD8⁺ T cell subset also exhibited a higher frequency of IFN-γ-producing and cytotoxic (Granzyme B⁺, Perforin⁺) cells. In contrast, the less immunogenic B16F10-OVA model did not show significant differences in tumor growth; however, CD39KO mice displayed an increased frequency of antigen-specific, pre-exhausted (PD-1^Int) CD8⁺ T cells, a population recognized as a key target of immunotherapy. Pharmacological CD39 blockade with POM-1, when combined with IL-2cx treatment to redirect IL-2 activity, enhanced the accumulation of pre-exhausted CD8⁺ T cells with cytotoxic potential, thereby improving tumor control. This combinatorial strategy also reshaped the tumor immune landscape by increasing activated NK cells, elevating Granzyme B expression in CD4⁺ T cells, and decreasing immunosuppressive M-MDSCs expressing CD39, CD38, and CD73. Collectively, our findings demonstrate that integrating purinergic pathway inhibition with IL-2-based immunotherapies can coordinately reprogram lymphoid and myeloid compartments, attenuate immunosuppressive mechanisms within the tumor microenvironment, and amplify antitumor immunity, providing a strong rationale for advancing this strategy toward clinical translation.

Chronic liver disease (CLD) represents a major global public health challenge, necessitating a systematic understanding of its complex immunopathological mechanisms. This review comprehensively summarizes the groundbreaking applications of cutting-edge technologies-including single-cell sequencing, spatial transcriptomics, and organoid models-in chronic liver disease immunology research: Single-cell sequencing resolves immune cell heterogeneity at unprecedented resolution, identifies rare cell subsets, and reveals dynamic changes and regulatory networks through multi-omics integration; Spatial transcriptomics complements this by mapping immune-stromal interactions within structural contexts such as the portal tract, fibrotic septa, and tumor niches, uncovering spatially organized immune evasion mechanisms and microenvironmental remodeling; Organoid technology constructs humanized liver-immune models that recapitulate disease-specific features-such as fibrosis, steatohepatitis, and hepatocellular carcinoma-enabling mechanistic validation, drug screening, and individualized therapeutic exploration. The synergistic integration of multi-omics profiling, spatial mapping, and organoid modeling is driving a paradigm shift in chronic liver disease immunology-transitioning from static cellular descriptions to spatiotemporal mechanism decoding, and from population-level insights to individualized pathophysiology and treatment prediction. These advanced approaches establish a technological foundation for building precision immunotherapeutic strategies tailored to spatiotemporal regulation of the liver immune microenvironment.

Background: Rheumatoid arthritis (RA) is a prototypical autoimmune disease characterized by chronic inflammation and immune dysregulation. Although Janus kinase (JAK) inhibitors such as tofacitinib have expanded therapeutic options, treatment responses remain heterogeneous and reliable predictors of efficacy are lacking.

Methods: Peripheral blood mononuclear cells (PBMCs) and serum samples were collected from 14 patients with active RA before initiation of tofacitinib treatment. Patients were classified as responders or non-responders according to EULAR DAS28 criteria after treatment. An integrative multi-omics approach was applied, including RNA sequencing, miRNA sequencing, proteomics, and untargeted metabolomics. Comprehensive bioinformatics analyses were performed to identify potential candidate predictors of tofacitinib response. Key findings were further assessed through internal validation in an independent cohort of tofacitinib-treated RA patients and external validation using publicly available datasets.

Results: Multi-omics analyses revealed upregulation of ribosomal proteins in PBMCs of responders, with RPL21 emerging as a potential immune-related candidate. Consistently, hsa-miR-197-3p and hsa-miR-625-3p were downregulated in responders, suggesting possible regulatory roles in treatment efficacy. Proteomic profiling showed decreased serum apolipoproteins, particularly APOA1, while metabolomic analysis identified elevated choline, malate, and nervonic acid, reflecting immune-metabolic reprogramming. Integration of multi-omics data highlighted convergent immune pathways and identified exploratory candidate biomarkers associated with tofacitinib response.

Conclusions: This study provides exploratory integrative multi-omics evidence linking immune-related transcriptomic, proteomic, and metabolic alterations to heterogeneous therapeutic responses in RA. The identified signatures improve our understanding of molecular pathways underlying JAK inhibition response and offer potential candidate biomarkers to guide personalized treatment strategies.

Introduction: Neoantigens from the Kirsten rat sarcoma viral oncogene homolog (KRAS) are specific cancer therapeutic targets. However, to date, no immune product targeting KRAS neoantigens has been approved for clinical use, and key challenges regarding efficacy and generalizability remain.

Methods: In this study, we isolated a natural human T-cell antigen receptor (TCR) 0 that specifically recognized human leukocyte antigen (HLA)-A*11:01+ T2 cells pulsed with KRAS G12V_8-16 peptides. However, TCR0 gene-transduced T cells demonstrated inadequate response to tumor cell lines. We generated T cells expressing a TCR0 mutant, being designated as TCR3.

Results: TCR3-T cells showed significantly optimized avidity and response to tumor cell lines, retained specificity for the KRAS G12V8-16 peptide with no response to normal cells, killed tumor cells that highly expressed programmed cell death-ligand 1 in vitro and in vivo, proliferated without being seriously affected by indoleamine 2,3-dioxygenase, resisted transforming growth factor β, and infiltrated and recruited other immune cells to the tumor site through chemokines.

Discussion: TCR3 may be useful for KRAS neoantigen-targeted clinical immunotherapy, help resolve cancer immune escape, and enhance clinical effectiveness and safety.

Background: Dermatomyositis (DM) is an autoimmune myopathy often linked to aberrant type I interferon (IFN) pathway activation. However, the molecular mediators driving this IFN signature and their utility as biomarkers remain incompletely defined.

Methods: We conducted an integrated multi-omics analysis combining plasma proteomics from 14 patients with DM and 5 healthy controls, with transcriptomic profiling of skeletal muscle derived from three publicly available Gene Expression Omnibus datasets (GSE11971, GSE1551, and GSE128470). Selected plasma proteins were further quantified and validated using enzyme-linked immunosorbent assay (ELISA).

Results: Proteomic profiling identified 482 differentially expressed proteins (DEPs). Upregulated DEPs were enriched in antiviral responses and IFN-related immune pathways, while downregulated DEPs were associated with extracellular matrix organization. Transcriptomic analysis revealed 156 consistently upregulated differentially expressed genes across datasets, primarily involved in innate immunity, nucleic acid sensing, and antigen presentation. Integrative analysis identified 2'-5'-oligoadenylate synthetase 3 (OAS3) as a central hub within the IFN signaling network. ELISA validation demonstrated significantly elevated plasma OAS3 levels in DM patients (median: 5.073 ng/ml, IQR: 2.93-9.36) compared with controls (median: 2.723 ng/mL, IQR: 1.77-3.34), with a P-value of 0.018. Notably, plasma OAS3 levels showed a positive correlation with serum creatine kinase concentrations (r=0.55, P = 0.044).

Conclusions: OAS3 expression was consistently elevated in both plasma and skeletal muscle tissues of individuals with DM. This molecule may act as a key enhancer of type I IFN-mediated pathogenic responses. Our results support the potential of OAS3 as a novel biomarker and therapeutic target in DM.