Immune Network最新文献

Coxsackievirus type B3 (CVB3) is implicated in diseases such as chronic myocarditis and pancreatitis. While IL-22 is known to play complex roles in immune responses during viral infections, its role in CVB3-induced pancreatitis remains unclear. This study examined the impact of IL-22 on pancreatic pathology during CVB3 infection using histological analyses, glucose tolerance tests, immunostaining, viral load quantification, and molecular assays in both mouse pancreatic tissues and HeLa cells. The results demonstrate that IL-22 exacerbates CVB3-induced pancreatitis by promoting viral replication and pancreatic injury. Mechanistically, IL-22 enhances CVB3 replication through recruitment of phosphatidylinositol 4-kinase III beta, mediated by STAT3 activation. These findings reveal a detrimental role for IL-22 in CVB3 infection, characterized by increased apoptosis, β-cell dysfunction, and elevated viral load, providing new insight into the pathogenesis of virus-induced pancreatitis.

Thioredoxin-interacting protein (TXNIP) functions as a tumor suppressor, but its role in lung cancer remains poorly defined. This study identifies TXNIP as a negative regulator of TNF receptor-associated factor 6 (TRAF6)-mediated NF-κB activation and autophagy, key pathways in tumor progression. TXNIP directly binds TRAF6 via its C-terminal arrestin domain, inhibiting TRAF6 dimerization and auto-ubiquitination. This, in turn, reduces ubiquitination of downstream targets TGF-β-activated kinase 1 and beclin 1 (BECN1), thereby suppressing NF-κB signaling and autophagic activity. TXNIP expression is significantly reduced in lung adenocarcinoma and lung squamous cell carcinoma, as demonstrated by public datasets and patient tissue analysis. Gene set enrichment analysis shows that non-small cell lung cancer patients with TXNIP^DOWN and TRAF6^UP expression exhibit increased metastasis-associated gene signatures and poorer survival outcomes. Functionally, TXNIP-knockout lung cancer cells show enhanced TRAF6 and BECN1 ubiquitination, increased LC3 puncta, and elevated NF-κB activity and cytokine production after TLR3/4 stimulation. These cells also display increased proliferation, migration, invasion, and colony formation in vitro across multiple lung cancer cell lines (A549 and H1299). Collectively, this study highlights TXNIP as a critical suppressor of TRAF6-driven oncogenic pathways in lung cancer, suggesting that its downregulation contributes to disease progression through enhanced TLR-induced signaling.

Complement anaphylatoxins C3a and C5a are potent immunomodulators whose impact extends well beyond their traditional roles in innate immunity. Acting through G protein-coupled receptors C3aR, C5aR1, and C5aR2, these peptides take part in coordinating immune cell recruitment, vascular tone, and tissue remodeling. Yet their functions are deeply context-dependent: while they play essential roles in microbial clearance and immune coordination, their overactivation contributes to immunopathology in a wide range of diseases. The anaphylatoxins play key roles in early pathogen containment but can also drive cytokine storm and tissue damage, as in coronavirus disease 2019 (COVID-19) and bacterial sepsis. In autoimmune conditions, the anaphylatoxins promote leukocyte infiltration and complement-mediated tissue injury. In chronic diseases, they contribute to fibrosis in diabetic kidney disease and idiopathic pulmonary fibrosis, and anaphylatoxins disrupt neurovascular integrity in neurodegenerative diseases. In cancer, C3a and C5a shape the tumor microenvironment by facilitating immune evasion, angiogenesis, and metastasis. As complement-targeted therapies gain momentum in clinical settings-particularly in the treatment of genetic disorders, such as paroxysmal nocturnal hemoglobinuria, more recently COVID-19, and cancer-a deeper mechanistic understanding of C3a and C5a signaling is imperative as we advance closer toward precision medicine, and this review aims to inform future approaches for therapeutic complement modulation.

Arginine, a conditionally essential amino acid, orchestrates critical metabolic networks in cancer biology and immunotherapy. Abnormalities in arginine metabolism are associated with cancer initiation, progression and immune escape. Polyamines and nitric oxide are the key metabolites with multiple regulatory effects on cancer cell growth and immune cells by driving metabolic reprogramming and promoting immune evasion in cancer cells. Targeting key enzymes and transporters in arginine pathways, along with arginine deprivation therapy, shows promise in preclinical and clinical studies. This review summarizes the regulatory mechanisms of arginine metabolism and evaluates its potential as a therapeutic target in cancer therapy. We specifically discuss the multifaceted roles of arginine and its metabolites in cancer progression, immune cell regulation, and immunotherapy, providing a theoretical foundation for its application in cancer prevention and treatment.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a curative potential for high-risk patients with leukemia following first-line therapies, driven by potent immune cell-dependent anti-tumour activities. Although deep remission can be achieved, many patients relapse after allo-HSCT, and further treatment options are scarce. Given the potent immune cell-mediated anti-leukemic effects of allo-HSCT, adoptive cellular therapies (ACTs) have been explored as an adjunctive therapy to enhance the efficacy of allo-HSCT or to treat patients who relapse after allo-HSCT. Interestingly, evidence suggests a stratified therapeutic approach is warranted between pediatric and adult leukemic cases, due to differences in genetic mutations and treatment tolerability. However, pediatric-specific investigations are limited, especially in the cellular therapeutic landscape to treat relapse after allo-HSCT. Known severe toxicities attributed to ACTs need to be addressed for this younger population to ensure prolonged quality of life. This review summarizes the current landscape of ACTs, including donor lymphocyte infusion, chimeric Ag receptor-T cell, NK cell, and double-negative T cell therapies, for treating pediatric leukemia post allo-HSCT, highlighting efficacy, safety, and gaps in pediatric-specific data to guide future research.

Developmental and epileptic encephalopathies (DEEs), including Infantile Epileptic Spasms Syndrome (IESS) and Lennox-Gastaut Syndrome (LGS), are severe pediatric conditions characterized by profound developmental delays and treatment-resistant epilepsy. Although steroid therapies provide some clinical benefits, the underlying immunological mechanisms remain poorly understood. In this study, we performed comprehensive immune profiling using multi-parametric flow cytometry on PBMCs from IESS (n=25) and LGS (n=9) patients, comparing them with age-matched healthy controls (n=54). Our findings identified distinct patterns of immune dysregulation: IESS patients exhibited reduced naïve CD4⁺ T cells, an altered CD4/CD8 ratio, and diminished TNFα production in CD4⁺ T cells. Conversely, LGS patients demonstrated an increase in central memory CD4⁺ T cells, marked dysfunction of Tregs, and heightened activation of CD8⁺ T cells. Notably, elevated activated CD8⁺ T cells in IESS patients correlated significantly with clinical severity and demonstrated enhanced responsiveness to viral peptides, suggesting prior viral infections may exacerbate disease progression. Collectively, our findings demonstrate distinct immune signatures associated with disease severity and progression in DEE, suggesting their potential utility as biomarkers. Further studies are necessary to determine whether targeting these immune pathways could provide clinical benefits.

The intestinal immune system is adapted to maintain constant interactions with environmental stimuli without causing inflammation. The recognition of Ags derived from microbes and diet can induce Treg or effector T cell responses through dynamic regulatory mechanisms, significantly impacting host health and disease. Although several examples of Ag-specific T cell responses to microbial or dietary Ags have been reported, our understanding of the full range of gut T cell responses remains highly limited. In this review, we highlight recent insights into the complexity of gut TCR responses. Different from traditional approaches, such as TCR transgenic mice and peptide MHC tetramers, our novel approach enables comprehensive analysis of entire repertoire of intestinal TCR responses, revealing both aggregated or individual TCR responses to different classes of Ags, which are regulated by bidirectional interactions between diet and microbiota.

Pediatric atopic dermatitis (AD) shows distinct clinical characteristics compared to adult AD, suggesting unique inflammatory profiles that may influence disease prognosis and treatment response. We aimed to identify unique immune signatures of pediatric AD and investigate the differences between pediatric and adult AD patients. Nine pediatric (6-16 years) and 12 adult (20-60 years) were enrolled. PBMCs were collected from AD patients and age- and sex-matched healthy controls (HCs). Transcriptomic profiles were analyzed using single-cell RNA sequencing, and the immune phenotypes of adult and pediatric AD were compared. Th2 gene expression was elevated in both adult and pediatric AD, while Th1, Th17, and Th22 gene expression was downregulated in pediatric AD but not in adults. Genes involved in JAK/STAT signaling pathway, which were upregulated in adult AD, were not significantly increased in pediatric AD. The CD6-activated leukocyte cell adhesion molecule (ALCAM) pathway was upregulated in pediatric AD compared to pediatric HCs, but not in adult AD. Pediatric AD reveals distinct immune signatures, including a lack of JAK/STAT pathway upregulation observed in adult AD and a unique activation of the CD6-ALCAM pathway. These findings highlight the importance of age-specific treatment strategies in AD patients.

Many studies of osteoarthritis (OA) have focused on the use of pain-suppressing drugs and stem cell treatments for cartilage repair. In a previous study, we reported the therapeutic effect of soluble C-C chemokine receptor type 2 (sCCR2) gene therapy on OA. Here, we aimed to demonstrate that sCCR2-expressing stem cells exhibits superior efficacy compared to mesenchymal stem cell (MSC) alone. We used monosodium iodoacetate to induce OA in a Wistar rat model for our experiments. Soluble form of CCR2 was transfected into chondrocytes. We analyzed both in vitro and in vivo systems using sCCR2 E3-transfected MSCs (sCEMs). MCP-1 reduced chondrogenesis, whereas sCEMs improved it. Additionally, disease development was suppressed in MCP-1 conditional knockout mice. In the OA rat model, injection of sCEMs showed significant effects with respect to pain control and reduction of joint cartilage inflammation and damage compared with injection of MOCK-MSCs. These findings indicate that sCEMs inhibit MCP-1, reducing pain and OA-induced cartilage damage and inducing chondroprotection. Inhibiting MCP-1/CCR2 signaling has a significant therapeutic effect on OA. Therefore, sCEM may be an effective treatment for OA.