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关键词： Immunology   Cell biology   Stem cell research  

摘要： Strong T cell receptor (TCR) and interleukin (IL)-27 signaling influence type 1 regulatory (Tr1) T cell development, but whether other signals determine their differentiation is unclear. Utilizing Tg4 TCR transgenic mice, we established a model for rapid Tr1 cell induction. A single high dose of [4Y]-MBP peptide drove the differentiation of Il10+ T cells with Tr1 cell mRNA and protein signatures. Kinetic transcriptional and phenotypic analyses revealed that the Tr1 cell module was transient and preceded by Ifng transcription in other CD4+ T cells. Changes in Tr1 cell frequency correlated with altered macrophage activation, while neutralization of interferon (IFN)y reduced Tr1 cell frequency and the TCR signal strength markers Nur77, inducible T cell costimulator (ICOS), and OX40. Antibody depletion experiments inferred that the relevant source of IFNy was not natural killer (NK) cell derived. Additionally, blocking IL-27 in combination with IFNy neutralization additively reduced Tr1 cell frequency in vivo. These findings reveal that IFNy has a non-redundant role in augmenting Tr1 cell differentiation in vivo.

关键词： Multiple sclerosis   IL2RA   rs2104286   Meta-analysis   Iranian population  

摘要： The interleukin-2 receptor alpha chain (IL2RA) gene has been implicated in multiple sclerosis (MS) susceptibility, particularly through the rs2104286 and rs12722489 SNPs. However, previous studies have yielded inconsistent results across different populations, likely due to small sample sizes and ethnic variations. This study aimed to investigate the association of IL2RA SNPs with MS risk in eastern Iranian population and through a comprehensive meta-analysis. Our case-control study included 400 Iranian individuals from North Khorasan and Sistan & Baluchistan provinces, comprising 200 MS patients across all subtypes and genders and 200 controls. The meta-analysis incorporated pooled odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the strength of these associations. Our case-control findings demonstrated a significant association between rs2104286 and MS risk, which was further supported by the meta-analysis in Iranian populations. Specifically, the association was observed at both the genotype (P = 0.001) and allelic (P = 0.003) levels in North Khorasan and at the genotype level in Sistan & Baluchistan (P = 0.001). A global meta-analysis of rs2104286, encompassing 24,931 MS patients and 36,036 controls, revealed a significant association between the A allele and all genotype models with increased MS risk (P < 0.05). Similarly, a meta-analysis of rs12722489, including 19,797 MS patients and 32,085 controls, identified the CC + CT genotype as a risk factor for MS (P = 0.04). In conclusion, our findings suggest that the rs2104286 A allele and rs12722489 CC + CT genotype are associated with an increased risk of MS in both Caucasian and Asian populations, including Iranians.

关键词： gastric cancer   machine learning   IL1RAP   tumor microenvironment   M2-type macrophages  

摘要： Background Investigating the pivotal role of IL1RAP in the tumor microenvironment of gastric *** Download and collate transcriptomic and single-cell data from gastric cancer patients. Three machine learning algorithms identified distinct sets of prognostic genes in gastric cancer patients. The CIBERSORT and ssGSEA algorithms elucidated immune infiltration patterns, while TIDE and TCGA predicted immune-related outcomes. Furthermore, single-cell sequencing data confirmed the interaction of IL1RAP within the tumor microenvironment. Finally, differential expression levels of IL1RAP protein and mRNA were *** After machine learning screening and independent dataset validation, high IL1RAP expression was identified as a poor prognostic factor for gastric cancer patients. Immune infiltration analysis indicated that the low IL1RAP expression group was associated with higher infiltration of CD8+ T cells and M1-type macrophages, whereas the high IL1RAP expression group exhibited increased presence of M2-type macrophages. Immunotherapy prediction models suggested a more favorable response to PD-1 treatment in the low IL1RAP expression group. Prognostic models incorporating IL1RAP demonstrated superior predictive performance. Single-cell data analysis revealed that IL1RAP plays a critical role in regulating intercellular communication within the tumor microenvironment. Our findings were further validated by confirming elevated IL1RAP expression levels in gastric cancer *** IL1RAP plays a critical role in the tumor microenvironment of gastric cancer and serves as a robust predictor of immunotherapy efficacy in gastric cancer.

关键词： Alcoholic liver disease   Flos puerariae   Exosomes-like nanoparticles   Pharmacodynamics   Mechanism  

摘要： Background: Alcoholic liver disease (ALD) represents the most severe and irreversible form of liver damage caused by alcohol consumption and has become a major global health issue, leading to high morbidity and mortality associated with liver disease. Flos Puerariae (FP), a traditional Chinese medicine has demonstrated therapeutic efficacy for treating ALD in various studies. Results: In this research, exosome-like nanovesicles derived from FP (FP-ELNs) were isolated and purified using differential centrifugation and ultracentrifugation techniques. The particle size of FP-ELNs was measured at 83.2 +/- 15.8 nm, with a concentration of 2.08 x 1011 particles/mL. A total of 112 lipids, 13 proteins, and 64 miRNAs were identified in FP-ELNs. These nanovesicles exhibited remarkable stability, enduring multiple enzymatic digestions, extreme pH conditions, and simulated gastrointestinal fluids. Bio-distribution analysis revealed that FP-ELNs primarily accumulated in the intestines, liver, kidneys, lungs, thymus, and spleen of mice following oral administration. In vitro, FP-ELNs reduced the level of ALT, AST, TC, and TG;decreased the production of TNF-alpha, IL-1 beta, IL-6, MDA, and ROS;enhanced the activities of SOD and GSH-Px;and downregulated CYP2E1 protein expression. These findings were also corroborated by in vivo experiments in mice. Notably, oral administration of FP-ELNs in ALD mice significantly reduced serum concentrations and hepatic expression of IL-11, an upstream pro-inflammatory cytokine with critical negative effects on ALD, age-associated disease, and lifespan. Conclusions: In conclusion, this study provides compelling evidence that FP-ELNs can mitigate alcohol-induced oxidative stress and inflammation by downregulating the IL-11-related signaling pathways in a PI3K/AKT/

关键词： cannabidiol   phenotype reversion   protein regulation   proteomics   mass spectrometry   protein networks   cancer treatment  

摘要： Cannabidiol (CBD) has shown promise in treating cancers with an inflammatory microenvironment. Although it has been demonstrated that IL-1 beta induces epithelial-mesenchymal transition (EMT) of MCF-7 cells and CBD reverts this process, in restoring the epithelial non-invasive phenotype, there is limited understanding of how this cannabinoid regulates these processes. In this work, MCF-7 cells were induced to adopt an aggressive phenotype (6D cells), which was reversed by CBD. Then, protein expression was analyzed by mass spectrometry to compare 6D vs. MCF-7 cells and 6D+CBD vs. 6D cells proteomes. Novel proteins associated with EMT and CBD signaling were identified. Twenty-four of them were oppositely regulated by IL-1 beta and CBD, suggesting new points of crosstalk between the IL-1 beta and CBD signaling pathways. From the data, two protein networks were constructed: one related to EMT with 58 up-regulated proteins and another with 21 related to CBD signaling. The first one showed the proteins BRCA1, MSN, and CORO1A as the key axis that contributes to the establishment of a mesenchymal phenotype. In the CBD signaling, the key axis was formed by SUPT16H, SETD2, and H2BC12, which suggests epigenetic regulation by CBD in the restoration of an epithelial phenotype of breast cancer cells, providing new targets for anticancer therapy.

关键词： Mast cells   Organoids   Co-cultures   TNF-alpha   IL-33   Intestinal differentiation and architecture  

摘要： It is common knowledge that mast cells (MCs) exert different roles in the gastrointestinal tract, from the maintenance of homeostasis to the onset and propagation of different gut diseases such as food allergies, infections, inflammation, and cancer. However, the mechanisms through which MCs dialog and influence the intestinal tissue are not completely known. To get insight into the bidirectional crosstalk between MCs and the intestinal microenvironment, both in homeostatic and pathological settings, colon organoids from intestinal epithelium of healthy mice and adenomas from AOM/DSS-treated mice have been exploited and co-cultured with MCs. The influence of MCs on organoid architecture and the effect of healthy and tumoral organoids on the phenotype and responsiveness of MCs have been addressed. We observed that MCs interact with intestinal organoids and contribute to the differentiation of healthy organoids by upregulating the expression of mucin-2, chromogranin A, cadherin-1, and claudin 4. On the contrary, in co-culture with tumoral organoids a decrease in cell proliferation, chromogranin A, and lysozyme expression was observed. Tumoral organoids have been shown to activate MCs via the IL-33/ST2 axis leading to increased release of TNF-alpha which in turn was responsible for the observed effects on tumoral organoids. Our results indicate that MCs are important mediators of intestinal tissue homeostasis and that a different environment can shape and direct MCs toward the dampening or propagation of the inflammatory response. Ultimately, our MC-organoid co-cultures represent a valid in vitro tool to investigate the role of MCs in the gut.

关键词： Artificial antigen-presenting cell   Natural killer cell   Acute myeloid leukemia   Cord Blood NK cells   NK-92 cells  

摘要： Acute myeloid leukemia (AML) is an aggressive malignancy with limited treatment options. Enhancing natural killer (NK) cell functionality through artificial antigen-presenting cells (aAPCs) represents a promising immunotherapeutic strategy. This study evaluates the potential of genetically modified K562 cells, expressing CD137L and CD86, to enhance NK cell-mediated cytotoxicity against AML cell lines (HL-60, KG-1, and THP-1). Lentiviral transduction was used to generate aAPCs, confirmed by PCR, RT-PCR, and flow cytometry. Cord NK cells and the NK-92 cell line were co-cultured with aAPCs, and their cytotoxicity against cell lines was assessed using 7-AAD staining. The ability of transduced K562 cells to substitute for interleukin-15 (IL-15) was also evaluated. These cells significantly enhanced NK cell-mediated cytotoxicity, with greater effects observed at higher effector-to-target (E:T) ratios. The aAPCs partially replaced IL-15 in activating cord blood NK cells but were ineffective for NK-92 cells. The aAPCs effectively enhance NK cell cytotoxicity and may reduce cytokine dependence in therapeutic applications. These findings highlight the potential of aAPCs to improve NK cell-based immunotherapies.

关键词： ticks   saliva   cytokine-binding proteins   immunomodulation   Amblyomma sculptum  

摘要： The saliva of hematophagous arthropods, such as ticks and triatomines, contains bioactive ligands capable of modulating immune molecules, including cytokines. Cytokines play a critical role in immune regulation and have therapeutic relevance in inflammatory and immune-mediated diseases. Despite recent advances, identifying cytokine-binding molecules remains a significant challenge. Interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and interleukin-17 (IL-17) are key cytokines involved in inflammation, adaptive immunity, and host defense. This study evaluated the ability of salivary components from Amblyomma sculptum and compared the results to the triatomine Rhodnius neglectus (used as control) to bind to IL-2, IL-4, IL-6, IL-10, IL-17, IFN-gamma, and TNF-alpha using ELISA assays with human cytokines. Saliva samples were tested at dilutions of 1:25, 1:50, and 1:100. Saliva from A. sculptum, which demonstrated significant anti-cytokine activity, was fractionated via HPLC to identify the active components. The results confirmed the inhibitory capacity of A. sculptum saliva on IFN-gamma, IL-4, and IL-17, with inhibition rates ranging from 30% to 70%, depending on the cytokine and dilution. No inhibitory activity was observed against IL-2, IL-6, IL-10, or TNF-alpha. These findings underscore the immunomodulatory role of A. sculptum saliva during tick feeding and suggest its potential for the development of novel immunobiologics to treat inflammatory and immune-mediated diseases.

摘要： The shared HLA-bound neoepitopes in pancreatic ductal adenocarcinoma (PDAC) represent a novel class of noncanonical antigens with single amino acid substitutions resulting from translational errors. These peptides, shared across patients with PDAC, showed higher immunogenicity than wild-type counterparts, offering potential candidates for specific immunotherapy development in PDAC. See related article by Zhang et al., p. 1956