Immune Network最新文献

An effective respiratory syncytial virus (RSV) vaccine should elicit neutralizing Abs and confer protection without causing vaccine-enhanced disease. Virus-like particle (VLP) is a safe vaccine platform that can display multivalent Ags similar to a virus and induce potent neutralizing Abs without adjuvant. We investigated the impact of mutations in the furin cleavage site, fusion (F) peptide, and change in the transmembrane (TM) domain of RSV F protein in VLPs on inducing RSV neutralizing Abs and efficacy in a cotton rat model. Palivizumab-binding antigenic site II epitope was preferentially exposed by combination mutations in the furin cleavage sites and F peptide together with a change in the TM domain. A single dose of mutant F protein VLP containing these combination mutations effectively induced IgG Ab responses to post-F and pre-F proteins, neutralizing activities, and protection without apparent lung histopathology. The VLP also induced the highest level of INF-γ, indicating the Th1-skewed immune response against the virus infection. A single dose of RSV F mutant exposing an antigenic site II on VLP vaccine could induce RSV-neutralizing Abs, conferring protection without causing vaccine-enhanced disease in cotton rats.

IL-33, a member of the IL-1 cytokine family, is constitutively expressed in the nucleus of various cell types. As an alarmin, IL-33 is released upon tissue damage and activates immune cell populations through its receptor, suppression of tumorigenicity 2 (ST2). Given that ST2 is expressed on diverse immune cells involved in both type 1 and type 2 immunity, IL-33 exerts pleiotropic effects on immune responses. In the tumor microenvironment (TME), IL-33 plays a dual role, promoting both protumor and antitumor TME. In this review, we summarize general characteristics of IL-33 and its immunological functions, with particular emphasis on its role in tumor immunity. Furthermore, we discuss recent advances in utilizing IL-33 in cancer immunotherapies and propose IL-33 as a potential candidate for the development of new cancer therapies.

Colorectal cancer (CRC), one of the most prevalent and lethal malignancies of digestive system, continues to impose a substantial burden on global health due to its high morbidity and mortality. Tumor microenvironment (TME) is a critical regulator for CRC progression and therapeutic response, but the in-depth understanding on the relationship of TME with CRC remains to be elucidated. In this study, we leveraged single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to dissect the immune heterogeneity in CRC patients. The differential expression genes analysis, functional enrichment analysis, random forest analysis and the Least Absolute Shrinkage and Selection Operator method were used to construct a molecular immune prognostic model. The molecular model demonstrated robust performance in stratifying patients based on their immune microenvironment characteristics. The experimental results showed that TIMP1 was highly expressed in CRC. Knockdown of TIMP1 gene significantly inhibited RKO cell proliferation and invasion. By integrating scRNA-seq and bulk RNA-seq data, we developed a new prognostic model that effectively predicts clinical outcomes in patients with CRC and identifies TIMP1 as a promising prognostic biomarker for CRC.

Ileal lipid binding protein (Ilbp), encoded by Fabp6 gene, plays a critical role in intracellular transport of bile acids (BAs) from apical to basolateral side of ileal enterocytes, maintaining BA homeostasis within enterohepatic circulation. However, pathophysiological consequences of Ilbp deficiency remain largely unexplored. Here, we demonstrate that disruption of BA balance, caused by intestinal epithelial cell (IEC)-specific Fabp6 gene knockout (Fabp6 ^ΔIEC), exacerbates dextran sulfate sodium (DSS)-induced gut inflammation. Fecal microbiota transplantation from Fabp6 ^ΔIEC mice to germ free recipient mice replicated the adverse effects observed in Fabp6 ^ΔIEC mice, which were mitigated when these mice were co-housed with control (Fabp6 ^f/f) mice. Metagenomic analysis identified Ligilactobacillus murinus as a primarily diminished strain in Fabp6 ^ΔIEC mice. Oral administration of L. murinus isolated from feces of Fabp6 ^f/f mice ameliorated DSS-induced colitis in Fabp6 ^ΔIEC mice by restoring epithelial barrier integrity and lowering pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Furthermore, daily administration of taurodeoxycholic acid-one of the BAs reduced in Fabp6 ^ΔIEC mice and that promotes the growth of L. murinus in an in vitro growth assay-also exhibited a protective effect against DSS-induced colitis through a similar mechanism. These findings suggest that deficiency of specific BAs due to epithelial Fabp6 deletion leads to gut dysbiosis, predisposing the host to inflammatory disease.

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.