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Results for “Treg cells”

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At least 19 recordsLinked to original sources

PubMed2025

Effect of Chang'an decoction on ulcerative colitis by regulating T helper 17 cells and regulatory T cellsRab27 in the p53/high mobility group box 1 pathway.

OBJECTIVE: To explore the effect of Chang'an decoction (, CAD) of ameliorating the immune imbalances in ulcerative colitis (UC) by regulating Rab27 in the P53/high mobility group box 1 pathway. METHODS: The functions and important signaling pathways of the Rab27- and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database, gene ontology database, Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis. Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results. Colon length, body weight, and disease activity index were measured. Hematoxylin and eosin staining was applied to validate the histopathology. Tight junction proteins were detected by immunohistochemistry. The proportions of T helper 17 cells (Th17) and regulatory T cells (Treg) in mesenteric lymph nodes were measured viaflow cytometry. Proinflammatory cytokines like interleukin (IL) 17 (IL-17), IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factor β and IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. The expression levels of high mobility group box 1 (HMGB1), P53 and phospho- P53 (P-P53) in colonic tissues were detected by immunofluorescence and Western blotting. RESULTS: Bioinformatics analysis revealed that compared with normal tissues, the expression of Rab27 was significantly increased in UC tissues. Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity. Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport, nutrient metabolism, transmembrane transport and the downstream pathway of P53. According to animal experiments, the expression of Rab27 was increased in UC tissues, which aggravated the colonic pathological damage, activated the expression of HMGB1, and also leaded to the imbalance of Th17 and Treg cells. After CAD intervention, Rab27 overexpression, weight loss, colon shortening, and pathological damage were substantial reduced, the expression of tight junction proteins, zona occludens 1 and Occludin were increased. The effect of CAD at high-dose was more obvious. In addition, CAD upgraded the number of Treg cells and the production of TGF-β and IL-10, while decreasing the number of Th17 cells and the expression of inflammatory cytokines (IL-17, IL-21, and IL-22). Moreover, colon inflammation was alleviated by CAD, as indicated by the regulation of HMGB1 and P-P53 expression. CONCLUSION: The expression of Rab27, HMGB1 and P-P53 could be decreased by CAD, and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.

Animals↗

PubMed2014

Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus.

The contribution of thymic antigen-presenting-cell (APC) subsets in selecting a self-tolerant T cell population remains unclear. We show that bone marrow (BM) APCs and medullary thymic epithelial cells (mTECs) played nonoverlapping roles in shaping the T cell receptor (TCR) repertoire by deletion and regulatory T (Treg) cell selection of distinct TCRs. Aire, which induces tissue-specific antigen expression in mTECs, affected the TCR repertoire in a manner distinct from mTEC presentation. Approximately half of Aire-dependent deletion or Treg cell selection utilized a pathway dependent on antigen presentation by BM APCs. Batf3-dependent CD8α⁺ dendritic cells (DCs) were the crucial BM APCs for Treg cell selection via this pathway, showing enhanced ability to present antigens from stromal cells. These results demonstrate the division of function between thymic APCs in shaping the self-tolerant TCR repertoire and reveal an unappreciated cooperation between mTECs and CD8α⁺ DCs for presentation of Aire-induced self-antigens to developing thymocytes.

Animals↗

PubMed2026

An inflammatory bowel disease-linked lncRNA suppresses transcription factor T-BET expression in T cells to limit intestinal inflammation.

Among the tens of thousands of annotated long noncoding RNAs (lncRNAs) in the human genome, only a small fraction have been functionally characterized. Here, we show that a well-established inflammatory bowel disease (IBD) risk locus encoded a conserved lncRNA, lnc15 (2310015A10Rik/ENSMUSG00000097729), whose structure was destabilized by risk-associated variants, leading to its degradation. Deletion of lnc15 in mice resulted in molecular features of inflammation under steady-state conditions and conferred heightened susceptibility to experimental colitis. Lnc15 was abundantly expressed in T cells, with highest expression in regulatory T (Treg) cells. Mechanistically, lnc15 suppressed the transcription factor T-BET by recruiting the CCR4-NOT RNA degradation complex to Tbx21 mRNA. Our study identifies that lnc15 simultaneously enhances Treg cell suppressive function and impairs conventional T cell pathogenicity in the context of intestinal inflammation. Collectively, these findings identify lnc15 as a functional lncRNA that links noncoding genetic variation to immune regulation and prevention of mucosal inflammation. VIDEO ABSTRACT.

RNA, Long Noncoding↗

PubMed2026

Role of CD25hi CD45RA+ CD4 not Treg %T cell in mediating the effect of pyruvate fermentation to acetone on intrahepatic cholangiocarcinoma.

This study aimed to elucidate the potential correlation between gut microbiota and intrahepatic cholangiocarcinoma (ICC) by investigating their causal relationship, while also exploring the possible role of immune cells as mediators in this association. We first identified gut microbiota based on phylum, class, order, family, and genus level information. Using summary-level data from a Genome-Wide Association Study (GWAS), we performed a 2-sample Mendelian randomization (MR) analysis of ICC and gut microbiota. Furthermore, we used 2-step MR to quantify the proportion of the effect of immune cell-mediated gut microbiota on ICC. MR analysis identified pyruvate fermentation to acetone (PFA) as predicting ICC risk reduction. There was no strong evidence that genetically predicted ICC had an effect on PFA risk. Furthermore, the proportion of genetically predicted PFA mediated by CD25hi CD45RA+ CD4 not Treg %T cell (CCCTT) was 3% (95% CI: 0.93-5.03%). In conclusion, our study established a causal relationship between PFA and ICC. We observed that a minor fraction of this effect was mediated by CCCTT, while the majority of the impact exerted by PFA on ICC remains elusive. However, further investigations are warranted to elucidate the mechanisms underlying the influence of gut microbiota on ICC development.

Cholangiocarcinoma↗

PubMed2025

Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA-TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA-TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA-TXNIP axis is a promising therapeutic target for improving cancer immunotherapy.

Tumor Microenvironment↗

PubMed2026

A Mendelian Randomization Study of Immune Cell Traits and Plasma Metabolites in Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT) is an autoimmune disorder of the thyroid. While immune cells are implicated in its pathogenesis, their specific roles have yet to be fully clarified. A two-sample Mendelian randomization (MR) analysis was conducted integrating genome-wide association study (GWAS) summary statistics from large public datasets for immune cell traits (ebi-a-GCST90001391 to ebi-a-GCST90002121), plasma metabolites (GCST90199621-9020102), and HT (ebi-a-GCST90018855). Causal effects were estimated using inverse-variance weighted (IVW) methods, with MR-Egger, weighted median, and leave-one-out analyses to assess pleiotropy and robustness. Bidirectional and mediation MR analyses were further applied to test directionality and identify potential metabolite-mediated pathways. CD3⁺CD4⁺CD25⁺CD39⁺Treg cells were quantified in peripheral blood samples using flow cytometry. Isovalerylcarnitine (C5) was measured by liquid chromatography tandem mass spectrometry. IVW analysis identified 32 immune cell phenotypes significantly associated with HT risk (P < 0.05 after FDR correction). Reverse MR analysis demonstrated that HT was positively causally linked with 2 immune characteristics, while 4 immune characteristics (all P < 0.05) were inversely associated with HT. Sensitivity analyses revealed no horizontal pleiotropy or heterogeneity. Additionally, the IVW method preliminarily identified 9 plasma metabolites as causally related to HT, including risk-enhancing C5 (OR = 1.120, 95% CI: 1.032-1.215, P = 0.006) and protective ergothioneine (OR = 0.958, 95% CI: 0.927-0.990, P = 0.010). Two-step MR mediation identified C5 as a candidate mediator connecting CD3⁺ CD39⁺ Treg to HT (mediation proportion 8.89%, 95% CI: 2.34%-15.4%, P = 0.008). Flow cytometry elevated CD39⁺Treg levels and plasma C5 in HT patients, with C5 positively correlated with CD39⁺Treg cells proportion. This study establishes novel causal links between immune cell phenotypes and HT, and highlights plasma metabolites, particularly C5, as potential mediators in HT pathogenesis. These findings deepen mechanistic understanding of autoimmune thyroid disease and may guide future biomarker and therapeutic target discovery.

Humans↗

PubMed2026

[Effects and mechanisms of Jiawei Yigong San on the Th17/Treg balance in food allergy].

Objective To explore the effects and mechanisms of Jiawei Yigong San (JWYGS) on the T helper type 17 (Th17)/regulatory T (Treg) cell balance in food allergy (FA). Methods Active components, action targets of JWYGS, and FA-related targets, were screened via network pharmacology. Overlapping targets between JWYGS and FA were used to construct a protein-protein interaction (PPI) network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed to predict key signaling pathways. Molecular docking was conducted to validate the binding affinity between the main active components and the predicted targets. Mice were randomly divided into control group, model group, JWYGS low-dose, medium-dose, and high-dose groups, and dexamethasone (DXM) group. An ovalbumin (OVA)-induced FA model was established. During the OVA challenge period, mice received daily intragastric administration, after which allergy and diarrhea scores were assessed. Small intestinal pathology was evaluated by HE staining. Serum ovalbumin-specific immunoglobulin E (OVA-sIgE), interleukin 6 (IL-6), IL-17, IL-2, and IL-10 were measured by ELISA. Small intestinal IL-6, IL-17, and IL-10 protein expression was detected by immunohistochemistry. Splenic Th17 and Treg cells were quantified by flow cytometry, and the Th17/Treg ratio was calculated. The mRNA expression of IL-6, retinoic acid receptor-related orphan receptor γt (RORγt), and forkhead box protein P3 (FOXP3) in the small intestine was detected by qPCR. Results Network pharmacology identified 235 active components of JWYGS and 136 common targets. GO and KEGG enrichment analyses highlighted cytokine response and Th17 differentiation. Molecular docking confirmed stable binding between core components and targets. Compared with the control group, the model group exhibited aggravated allergy and diarrhea scores, marked small intestinal inflammation and mucosal damage, elevated serum levels of OVA-sIgE, IL-6, IL-17 and IL-2, along with increased splenic Th17 cell frequency and Th17/Treg ratio. Intestinal IL-6 and IL-17 protein levels as well as IL-6 and RORγt mRNA expression were upregulated, whereas serum IL-10 levels were decreased, and intestinal expression of IL-10 protein and FOXP3 mRNA was downregulated. After JWYGS treatment, allergy and diarrhea scores were significantly reduced. Small intestinal inflammation and mucosal damage were alleviated. Serum levels of OVA-sIgE, IL-17, IL-6 and IL-2, Th17 cell frequency and the Th17/Treg ratio, intestinal IL-6 and IL-17 protein levels were decreased. IL-6 and RORγt mRNA expression was downregulated. Serum IL-10 levels were increased and intestinal expression of IL-10 protein and FOXP3 mRNA was upregulated. Moreover, the JWYGS high-dose group demonstrated comparable efficacy to the DXM group. Conclusion JWYGS can ameliorate symptoms and reverse the Th17/Treg imbalance in FA mice, potentially by inhibiting IL-6 transcription and regulating RORγt/FOXP3 expression.

Animals↗

PubMed2026

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗

PubMed2026

The mechanism of malignant progression in extramammary Paget's disease (EMPD): hallmarks of EMPD.

The pathogenesis of cancer is characterized by the acceleration of tumor growth, inhibition of tumor suppression, genetic and epigenetic alteration, lubricative transformation and tumor microenvironment. Extramammary Paget's disease (EMPD) is a rare skin cancer that originates from apocrine glands in genital and axillary area. Although the pathogenesis of EMPD is still poorly understood, increasing evidence reveals that the mechanism of EMPD progression is regulated by the acquired ability of EMPD cells and tumor microenvironment. HER2/PI3K/AKT signaling and hormone receptor pathways are activated. Whereas tumor mutation burden is low, numerous driver genes such as ERBB2 and PIK3CA are detected. Tumor evolution in EMPD is characterized by high genetic intratumor heterogeneity with shared background factors. Tumor microenvironment in EMPD promotes immune evasion through the reduction of reduced CD4 + and CD8 + T cells and the increase of Treg cells and CD163 + macrophages. Enhanced Warburg effect and S. aureus contribute to the suppression of antitumor immunity. This review focuses on the mechanism of malignant progression in EMPD (hallmarks of EMPD).

Genome mutation↗

PubMed2026

TGF-β and IL-2 differentially shape T follicular regulatory cell differentiation and stability in vitro.

T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells play critical roles in regulating the activity of the germinal center (GC), which is essential for the generation of high-affinity antibodies. In the GC, Tfh cells help B cells to proliferate and to differentiate into memory B cells and long-lived plasma cells. In contrast, Tfr cells, a specialized subset of regulatory T cells (Tregs), modulate the humoral immune response by suppressing excessive or autoreactive B-cell activity. Here, we established an in vitro differentiation protocol for mouse CD4⁺ T cells that yielded CXCR5⁺FoxP3⁺ Tfr cells that exhibited a Bcl6hiPD-1hiCD25loGITRint phenotype and were distinct from Treg and Tfh cells. Functionally, in vitro-generated Tfr cells potently suppressed Tfh cell-driven B-cell class switching to IgG1 and downregulated the expression of B-cell costimulatory ligands. While in vitro-generated Bcl6-deficient Tfh cells were impaired in providing help to B cells for efficient class switching to IgG1, in vitro-generated Bcl6-deficient Tfr cells failed to inhibit Tfh cell-driven B-cell class switching to IgG1. Mechanistically, we showed that Tfr cells emerged from FoxP3+ precursors in low-IL-2 environments through a TGF-β- and c-Maf-dependent pathway, allowing for reprogramming and reinforcement of the follicular regulatory cell program in CD4+ T cells in vitro.

Animals↗

PubMed2026

A Functionally Constrained Immune Ecosystem in Microsatellite-stable Colorectal Cancer Resolved by Single-cell and Exome Profiling.

BACKGROUND/AIM: Microsatellite-stable (MSS) colorectal cancer (CRC) generally responds poorly to immune checkpoint blockade, but some MSS tumors are T-cell rich. We examined whether such infiltration reflected effective immunity or functional immune constraint. CASE REPORT: A 77-year-old woman underwent resection of a mismatch repair-proficient (pMMR), MSS, low-mutational-burden CRC with a synchronous adenoma. Whole-exome sequencing of tumor, adenoma and adjacent normal tissue detected no shared high-confidence somatic mutations between tumor and adenoma within the sensitivity of this WES analysis and identified tumor-specific APC, KRAS and TP53 alterations. Tumor single-cell RNA sequencing yielded 7,569 cells, with T-lineage populations comprising 83.5%. Cytotoxic T cells showed cytolytic and dysfunction-associated features, regulatory T cells (Tregs) showed suppressive remodeling, and Th17 cells showed inflammatory/profibrotic programs. CellChat nominated stromal MIF/FN1-CD74/CD44 and extracellular-matrix communication with T-cell compartments. CONCLUSION: This molecular case report shows that T-cell abundance and immune effectiveness can be uncoupled in MSS CRC.

Humans↗

PubMed2026

Papillary Thyroid Carcinoma with Terminal Immune Exhaustion Phenotype Correlates with Increased Risk of Lymph Node Metastasis: An Exploratory Study Combining Flow Cytometry and TCGA.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with lymph node metastasis (LNM) being a key predictor of recurrence and poor prognosis. Preoperative detection of LNM remains challenging due to the limitations of imaging modalities, leading to inadequate surgical resection in 20-30% of patients. While immune checkpoint molecules have been implicated in PTC progression, the heterogeneity of CD8+ T cell exhaustion subsets and their specific association with LNM remain poorly defined. In this study, we aimed to perform an exploratory characterization of the distinct immune landscape of PTC prone to LNM, with a focus on terminal immune exhaustion, in order to generate hypotheses for improved risk stratification and therapeutic strategies. METHODS: Fresh PTC tissues from 40 patients (22 LNM-positive and 18 LNM-negative) were analyzed via flow cytometry (FCM) to quantify immune cell subsets, inflammatory cytokines, and chemokines. Immunohistochemistry (IHC) validated CD45+ immune cell infiltration. Transcriptomic and clinical data from 448 PTC patients in The Cancer Genome Atlas (TCGA-PTC) cohort were used for bioinformatic analysis consistent with the observed phenotype, including Gene Set Variation Analysis (GSVA) of terminal exhaustion gene signatures. RESULTS: LNM-positive PTC exhibited a unique inflammatory milieu with significantly elevated IL-6, IL-1ra, CCL5, and IL-9 levels (all p < 0.05) in tumor interstitial fluid. FCM analysis revealed that LNM-positive PTC had increased infiltration of total CD45+ immune cells, CD3+ T cells, and CD3+CD8+ T cells (all p < 0.05). Critically, terminally exhausted PD-1hiTIM-3+ CD8+ T cells were significantly enriched in LNM-positive PTC (p = 0.022) and positively correlated with extrathyroidal extension (p = 0.044). Additionally, LNM risk was associated with increased CD4+ regulatory T (Treg) cell frequency (p = 0.023) and elevated CTLA-4 expression on CD4+ T cells (p = 0.047). In TCGA-PTC validation, the terminal exhaustion gene signature was predominantly enriched in LNM-positive (p < 0.0001) and advanced-stage PTC (p < 0.001) and strongly correlated with BRAF mutation (predominantly V600E) (p < 0.0001)-the most common oncogenic driver in aggressive PTC. CONCLUSIONS: Our findings suggest a terminal immune exhaustion phenotype (characterized by PD-1hiTIM-3+ CD8+ T cells and Treg enrichment) as a potential key feature associated with LNM-prone PTC. This phenotype shows consistency across clinical samples and TCGA datasets, linking BRAF mutation (predominantly V600E) to immune suppression and metastatic potential. These insights provide a novel exploratory immune-based biomarker for LNM risk stratification and support the potential of combining anti-PD-1/TIM-3 therapy with BRAF inhibitors for high-risk PTC, which should be confirmed in future studies.

lymph node metastasis↗

PubMed2023

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. METHODS: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. RESULTS: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. CONCLUSION: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

Mice↗

PubMed2026

OLFML2B promotes hepatocellular carcinoma malignancy via the PI3K/AKT-EMT axis and correlates with an immunosuppressive tumor microenvironment.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality, highlighting the need for novel biomarkers and therapeutic targets. METHODS: The role of Olfactomedin-like 2B (OLFML2B) in HCC was investigated through multi-database analyses (The Cancer Genome Atlas, International Cancer Genome Consortium, Gene Expression Omnibus) and experimental validation. RESULTS: OLFML2B was significantly upregulated in HCC tissues, correlated with poor overall and disease-specific survival, clinicopathological features (tumor grade, stage, age, gender), and robust diagnostic performance (AUC > 0.7 across 14/15 datasets). Transcriptomic and single-cell analyses further revealed that high OLFML2B expression was associated with an immunosuppressive tumor microenvironment, characterized by increased infiltration of M2 macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as reduced abundance of cytotoxic T cells and NK cells. Knockdown of OLFML2B suppressed malignant phenotypes, including cell proliferation, migration, invasion, and angiogenesis, attenuated PI3K/AKT-EMT signaling, and enhanced sensitivity to sorafenib, cabozantinib, and regorafenib in Huh7 and HepG2 cells. Additionally, OLFML2B knockdown suppressed tumor growth and metastasis in zebrafish xenografts. DISCUSSION: Collectively, these findings indicate that OLFML2B is required for HCC progression and represents a prognostic biomarker and potential therapeutic target.

Humans↗

PubMed2026

Integrated single-cell and bulk transcriptomic analysis identifies a novel senescent fibroblast subtype associated with poor prognosis in acral melanoma.

BACKGROUND: Acral melanoma (AM) exhibits significant intratumoral heterogeneity, but its tumor microenvironment (TME) and immune regulation remain unclear. This study aims to dissect TME heterogeneity and establish a prognostic model based on key cell subpopulations. METHODS: We collected AM single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). Unsupervised clustering, CellChat, and Scissor analysis were performed to characterize cellular heterogeneity, cell-cell communication, and prognosis-related cell subpopulations. Kaplan-Meier analysis was used to assess the prognostic value of key genes, which were further validated by multiplex immunohistochemistry (mIHC). RESULTS: In AM, Mel_C2, C7, and C9 with high SEMA6A and KIT expression were strongly linked to poor prognosis. We further identified a senescent fibroblast subpopulation (sCAF_CDKN2A) characterized by high fibroblast senescence signature (FSS) scores. Integrating Scissor analysis of fibroblast subtypes with bulk prognostic data, we identified COL3A1, VCAN, and KIT as prognosis-associated genes upregulated in poor-outcome-related fibroblast subsets. Cell-cell communication analysis revealed that sCAF_CDKN2A engages in an immunosuppressive network, interacting with regulatory T cells (Tregs) via MIF signaling and receiving signals from exhausted CD8+ T cells through PPIA-BSG interactions. Using transcription factor expression patterns from these fibroblast subtypes, we constructed a prognostic model that effectively stratified patients into distinct risk groups with significant differences in overall survival (OS). mIHC confirmed significantly higher protein levels of SEMA6A and COL3A1 in tumor tissues compared to matched normal tissues. CONCLUSIONS: We established a novel prognostic model for AM and identified sCAF_CDKN2A as an immunosuppressive senescent fibroblast subpopulation driving poor prognosis.

Acral melanoma↗

PubMed2022

A Distinctive γδ T Cell Repertoire in NOD Mice Weakens Immune Regulation and Favors Diabetic Disease.

Previous studies in mice and humans suggesting that γδ T cells play a role in the development of type 1 diabetes have been inconsistent and contradictory. We attempted to resolve this for the type 1 diabetes-prone NOD mice by characterizing their γδ T cell populations, and by investigating the functional contributions of particular γδ T cells subsets, using Vγ-gene targeted NOD mice. We found evidence that NOD Vγ4+ γδ T cells inhibit the development of diabetes, and that the process by which they do so involves IL-17 production and/or promotion of regulatory CD4+ αβ T cells (Tregs) in the pancreatic lymph nodes. In contrast, the NOD Vγ1+ cells promote diabetes development. Enhanced Vγ1+ cell numbers in NOD mice, in particular those biased to produce IFNγ, appear to favor diabetic disease. Within NOD mice deficient in particular γδ T cell subsets, we noted that changes in the abundance of non-targeted T cell types also occurred, which varied depending upon the γδ T cells that were missing. Our results indicate that while certain γδ T cell subsets inhibit the development of spontaneous type 1 diabetes, others exacerbate it, and they may do so via mechanisms that include altering the levels of other T cells.

Mice↗

PubMed2024

Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4+ regulatory T cells by regulating IL2RA.

Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3, CTLA4, and PDCD1), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3), and loss of Treg-mediated suppression.

Humans↗

PubMed2026

CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.

Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.

Humans↗