Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs and involving both innate and adaptive immunity. Dendritic cells (DCs) play a crucial role in linking innate and adaptive immune responses, and therefore they deeply participate in the initiation and development of SLE. Deleted in breast cancer-1 (DBC1) is a negative regulator of deacetylase SIRT1 (the mammalian homolog of silent information regulator 1) and involves in tissue inflammation. Roles of DBC1 in immune cells remain largely unknown, especially in DCs. We here identified that DBC1 is upregulated in activated DCs, and DBC1 deficiency weakened DC maturation while promoting B7-H1 expression. DC conditional knockout of DBC1 ameliorated murine lupus pathology by decreasing autoantibodies, complement C3, plasma cells, and follicular T helper (Tfh) cells, whereas promoting regulatory T-cell development. We further demonstrated that Dbc1-/- DC lowered proinflammatory cytokine secretion such as IL-4, IL-6, and IL-12, and reduced signal transducer and activator of transcription 5 (STAT5) signal. With STAT5 overexpression, the protective effect by Dbc1-/- DC was abolished in the lupus model. Therefore, targeting the DBC1-STAT5 axis in DCs diversifies the therapeutic strategies for SLE.

Autoimmune inflammation results from dysregulated immune responses, with dysfunction of regulatory T cells (Tregs) being a key contributor due to their critical role in maintaining immune tolerance. The stability and function of Tregs are strongly influenced by the inflammatory microenvironment, yet the regulatory interactions between CD8+ T cells and CD4+Foxp3+ Tregs remain poorly understood. We investigated the role of CD8+ T cells in regulating induced Tregs (iTregs) using in vitro T cell co-culture assays and two in vivo models of autoimmune disease. A naïve CD4+ T cell transfer colitis model was used to evaluate the suppressive function of iTregs in the presence or absence of CD8+ T cells, while an autoimmune arthritis model was employed to assess therapeutic efficacy. Flow cytometry, functional suppression assays, and mechanistic analyses were performed to define signaling pathways. CD8+ T cells promoted the differentiation of a CD39+ iTreg subset characterized by increased frequencies of CD103, CTLA-4, and Helios, leading to enhanced immunosuppressive capacity. In the colitis model, co-transfer of CD8+ naïve T cells alleviated disease by reinforcing iTreg-mediated suppression of Th1 and Th17 responses. Mechanistic studies revealed that CD8+ T cells regulated iTreg phenotype through a ROS/TGF-β signaling axis, with IRF4 in CD8+ T cells acting as a key mediator. Importantly, CD8+ T cell–primed iTregs showed superior therapeutic efficacy in the autoimmune arthritis model by suppressing pathogenic Th1/Th17 responses and supporting endogenous Treg homeostasis. This study identifies a previously unrecognized role of CD8+ T cells in enhancing iTreg differentiation, stability, and suppressive function through the ROS/TGF-β–IRF4 pathway. These findings reveal a novel mechanism of immune regulation and suggest that harnessing CD8+ T cell–primed iTregs could represent a promising strategy to strengthen Treg-based therapies for autoimmune diseases.

The clinical utility of mesenchymal stem cells (MSCs) is often limited by pulmonary entrapment and poor systemic distribution, particularly in diseases constrained by physiological barriers such as rheumatoid arthritis (RA), where joint accessibility restricts therapeutic efficacy. This study systematically compares the immunomodulatory capacity and inflammation-targeting potential of human gingiva-derived MSCs (GMSCs) and their extracellular vesicles (GMSC-EVs) in vivo. Using an experimental RA model, we demonstrate that GMSC-EVs exhibit superior tropism to inflamed joints compared to GMSCs, resulting in significantly greater amelioration of disease severity, including reduced joint swelling, bone destruction, and balanced pathogenic T-cell responses. Mechanistically, we identify C-C chemokine receptor type 2 (CCR2) as the critical molecular driver of this targeted homing. Genetic ablation of CCR2 via CRISPR-Cas9/sgRNA knockdown abolishes both the joint-specific accumulation of GMSC-EVs and their therapeutic efficacy. These findings elucidate the molecular basis for GMSC-EVs tropism to arthritic lesions and establish CCR2 as a pivotal target for developing precision-engineered EVs therapies with enhanced specificity for RA treatment.

Background: T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase, is aberrantly overexpressed in human tumors and promotes malignant proliferation. Melanoma is a highly immunogenic tumor in which CD8+ T cell-mediated cytotoxicity is usually less effective in tumor control and responsive to immune checkpoint blockade. It is unclear whether the expression and functional characterization of TOPK within the immune cells affect the tumor microenvironment (TME) in patients with melanoma. This study aims to elucidate the expression pattern and immunoregulatory function of TOPK in CD8+ T lymphocytes during antitumor responses. Methods: Public single-cell RNA-sequencing (scRNA-seq) dataset analysis and flow cytometry assessed TOPK in tumor-infiltrating CD8+ T cells from patients with melanoma. Genetic deletion and pharmacological inhibition of TOPK using HI-TOPK-032 tested T cell-mediated melanoma control. Flow cytometry and tumor cell coculture killing assays measured effector release and target-cell apoptosis. Mechanistic analyses included assessment of interferon regulatory factor 5 (IRF5) expression, together with combination therapy using a programmed cell death protein 1 (PD-1)-blocking antibody in vivo. scRNA-seq of tumor-infiltrating lymphocytes (TILs) from Topkfl/fl and Cd8CreTopkfl/fl mice was also performed to define TOPK-dependent immune programs within the melanoma TME. Results: Single-cell transcriptomes identified a TOPK+ subset of tumor-infiltrating CD8+ T cells in melanoma, which was higher than that in normal lymph nodes (LNs), and exhibited suppressed cytotoxic and cytokine programs. CD8+ T cell-specific Topk deletion increased granzyme B (GzmB), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) secretion and improved tumor control. TOPK-deficient CD8+ T cells showed elevated activation-associated signaling pathways and immune effector gene expression. In murine TIL scRNA-seq, Cd8CreTopkfl/fl tumors exhibited increased effector and activation programs, reduced exhaustion and dysfunction programs, and enhanced immune crosstalk in the TME. Mechanistically, TOPK suppressed IRF5 expression and HI-TOPK-032 restored CD8+ T cell cytotoxicity in vitro and, with anti-PD-1, further inhibited tumor growth and increased intratumoral cytokine production. In human CD8+ T cells, enforced TOPK expression impaired cytotoxicity and cytokine secretion, reversed by IRF5 coexpression. Conclusions: These findings establish TOPK as the immune checkpoint limiting CD8+ T cell functionality in tumors and indicate the potential of TOPK inhibition as a strategy to augment T cell-based immunotherapies.

Background:Restoring immune homeostasis is crucial for inflammation resolution, in which B cells play dual regulatory roles. A promising therapeutic strategy involves simultaneously suppressing proinflammatory B-cell activity while enhancing regulatory B cells (Bregs). Natural anti-inflammatory compounds, such as the flavonoid apigenin (API), may achieve this dual immunomodulation, yet the precise mechanisms of API on B cells remain incompletely understood. Purpose:This study aimed to elucidate how API modulates B cells to exert immunoregulatory and protective effects in inflammatory conditions. Design:In vitro B-cell functional and molecular assays were integrated with two mechanistically distinct in vivo models-collagen-induced arthritis (CIA) in DBA/1 mice and cecal ligation and puncture (CLP)-induced sepsis in C57BL/6 mice-to evaluate API's dual immunomodulatory effects and therapeutic potential. Methods:B cells from mouse splenocytes (n=5 per group) or human PBMCs (n=5 healthy donors) were assessed for differentiation, cytokine production, class switch recombination (CSR), and signaling pathways. p38 MAPK involvement was examined using pathway-specific inhibitors. In vivo, disease severity, survival, immune phenotypes, cytokines, and histopathology were evaluated. Results:API increased IL-10⁺ Breg frequency by ~2-fold (P < 0.001) and reduced Aicda expression by ~60% (P < 0.001), while suppressing plasma cell differentiation via Prdm1 downregulation. These effects were p38 MAPK-dependent. In CIA mice, API reduced arthritis scores by ~45% (P < 0.01); in CLP-induced sepsis, 7-day survival improved from 0% to 70% (P < 0.05), with attenuated lung injury and pro-inflammatory cytokine levels. Collectively, API promotes immune homeostasis restoration in both chronic autoimmune and acute inflammatory settings. Conclusion:API restores immune homeostasis in both chronic autoimmune and acute inflammatory settings by coordinating Breg differentiation and suppressing pathogenic B-cell responses, highlighting B-cell-centric immune rebalancing as a promising therapeutic strategy for inflammatory diseases.

While classical tumor suppressors in colorectal cancer (CRC) are predominantly recognized for restraining cell-autonomous proliferation, their extrinsic mandate in orchestrating the tumor immunometabolic niche remains poorly defined. Clinically, we document that APC membrane recruitment protein 1 (AMER1) downregulation correlates with advanced progression and cytotoxic CD8+ T cell spatial exclusion in CRC patients. Using parallel homograft models in diverse host immune backgrounds, we show that tumoral AMER1 confers robust in vivo tumor-suppressive effects that are dependent on a fully functional immune system. Single-cell RNA sequencing reveals that tumoral AMER1 enrichment actively preserves CD8+ T cell effector stemness by expanding the CXCR5+ precursor exhausted subset (Tpex) across regional lymph nodes and primary tumor microenvironments. Integrated multi-omics and biochemical tracking identify dopamine (DA) as the conserved neurometabolic effector driving this niche remodeling. Mechanistically, AMER1 physically binds and rescues dopa decarboxylase (DDC) from post-translational degradation to sustain tumoral DA secretion; conversely, AMER1 loss creates a localized DA void. Cell-autonomously, tumoral DA accumulation triggers Gasdermin D (GSDMD)-dependent tumor pyroptosis. Therapeutically, local DA administration halts multi-lineage carcinoma progression by reversing CD8+ T cell terminal exhaustion and reinforcing central memory differentiation. Collectively, our findings redefine AMER1 as a critical immunometabolic gatekeeper and establish neurotransmitter metabolic bypassing as a promising therapeutic strategy for CRC.

As a pivotal tumor suppressor, p53 plays a critical role in the progression of lung adenocarcinoma (LUAD). However, the mechanisms through which its interacting partners modulate p53 transcriptional activity remain poorly understood. In this study, we identified the transcription factor FOXN3 as a key partner that recruits p53 for transcriptional responses. FOXN3 directly interacts with p53, and the two factors exhibit extensive genome-wide colocalization in both lung cancer cells and clinical tumor tissues, thereby co-regulating the transcription of numerous genes. Notably, nearly all p53 point mutants with disrupted DNA-binding capacity show markedly reduced association with FOXN3, underscoring the essential role of FOXN3 in facilitating p53 binding to DNA. Conditional knockout of FOXN3 promotes lung cancer cell survival, invasion, and tumorigenesis. Importantly, the regulation of p53 transcriptional activity by FOXN3 requires phosphorylation at the S83 and S85 sites. This phosphorylation induces the dissociation of FOXN3 from chromatin, thereby inhibiting p53 transcriptional recruitment and activation. Ablation of FOXN3 S83 and S85 phosphorylation impedes the progression of LUAD. Furthermore, increased phosphorylation of FOXN3 at S83 and S85 is observed in clinical lung tumor tissues and correlates with poor prognosis in patients with LUAD, highlighting its potential as a therapeutic target.

Background Carboxyl terminus of HSC70-interacting protein (CHIP) serves as a quality control protein that involves in inflammation and immunity, bone remodeling and tumorigenesis. However, the role of CHIP in joint disease such as rheumatoid arthritis (RA) is less explored. Methods Wild-type and Chip knockdown mice were used to establish a collagen-induced arthritis (CIA) model to assess arthritis progression through clinical index and histopathological markers (synovial hyperplasia, inflammatory infiltration and cartilage damage). SiRNA and lentivirus were respectively used to knockdown and overexpress CHIP in CIA fibroblast-like synoviocytes (FLS), investigating its regulatory effect on proliferation, migration, invasion and inflammation. Western blotting and immunofluorescence analysis were performed to assess the effect of CHIP on Tumor necrosis factor receptor-associated factor 6 (TRAF6) and to elucidate the underlying mechanism. Adeno-associated virus (AAV) mediated delivery of Chip was used to evaluate its therapeutic effects in CIA mice. Results CHIP significantly decreased in the synovium of CIA mice and RA patients compare to control. CHIP deficiency exacerbated synovial inflammation, cartilage degradation, and bone erosion in CIA, further underscoring its protective role in joint homeostasis. Moreover, knockdown of CHIP promoted the proliferation, migration and expression of inflammatory cytokines in CIA-FLS, while CHIP overexpression in CIA-FLS showed the opposite results. Mechanistically, CHIP interacted with TRAF6 and promoted the degradation of TRAF6. CHIP inhibited the migration and pro-inflammatory phenotypes of CIA-FLS via TRAF6/p65 pathway. Further, AAV mediated CHIP gene therapy by intra-articular administration effectively attenuated the progression of CIA by inhibiting the synovial inflammation and expression of TRAF6. Conclusion Collectively, these findings demonstrated the critical regulatory role of CHIP in RA. Therefore, exploiting the protective effects of CHIP may represent a potential therapeutic strategy for RA. The translational potential of this article These findings not only advance our understanding of CHIP's regulatory role in RA but also highlight the value of genetic animal models in orthopaedic drug discovery.

ABSTRACT In rheumatoid arthritis (RA), regulatory T cells (Tregs) within the synovium present a paradox: they are numerically enriched yet functionally impaired, leading to a loss of immune tolerance. Here, we report that synovial iron overload establishes a ferroptosis‐permissive microenvironment that disrupts Treg homeostasis. Exposure to RA synovial fluid induced ferroptosis, autoimmune Treg‐associated metabolic shifts through lipid peroxide‐driven mitochondrial dysfunction, characterized by electron transport chain (ETC) collapse and impaired oxidative phosphorylation. Mechanistically, metabolic disturbance by ferroptotic stress or complex III blockade triggered TXK kinase upregulation, which is required for the phosphorylation of STAT3 (Tyr705) and PLCγ1 (Tyr783), activating a proinflammatory transcriptional program that destabilized Treg identity and promoted Th17‐like conversion. Crucially, this pathogenic reprogramming was reversed through iron chelation or TXK inhibition in vitro and in vivo. Our findings unveil a ferroptosis‐ETC‐TXK/STAT3 axis as a core mechanism of synovial Treg failure. Targeting synovial iron homeostasis or inhibiting TXK signaling thus represents a promising therapeutic strategy to restore immune tolerance in RA by rescuing Treg functionality.

Abstract Introduction Regulatory T cells (Tregs) maintain immune homeostasis through FOXP3-centered transcriptional complexes that tightly control lineage stability and suppressive function. However, how specific FOXP3 mutations disturb this complex and drive pathogenic Treg reprogramming in IPEX syndrome remains unclear. We identified a distinctive mechanism by which the FOXP3 V408M mutation promotes Th1-skewed inflammation and also explored a pharmacological strategy to restore Treg stability. Methods We generated FOXP3 V408M knock-in mice and performed immunophenotyping, transcriptomic, and chromatin conformation analyses to determine how the mutation affects FOXP3—T-bet interaction and Ifng transcription. An AI-driven virtual screening strategy integrating sequence- and structure-based modeling was applied to identify compounds that stabilize FOXP3—T-bet interaction. Functional validation was performed in vitro and in multiple in vivo mouse models. Results FOXP3 V408M mutation disrupted the FOXP3—T-bet interaction, thereby releasing T-bet from FOXP3-mediated repression and enhancing Ifng transcription. This defect reprogrammed Tregs toward an IFN-γ—producing phenotype that promoted Th1 inflammation. Among the AI-driven screening hits, 430C10 emerged as a first-in-class FOXP3-targeting stabilizer binding an allosteric pocket within the FKH domain. 430C10 reinforced the FOXP3—T-bet interaction and suppressed T-bet—driven IFN-γ production by Tregs. Oral 430C10 treatment markedly alleviated IFN-γ+ Treg—driven inflammation in FOXP3 V408M mice and improved disease outcomes in an acute colitis model under FOXP3 WT settings. Conclusion Our findings define the FOXP3—T-bet interaction as a tunable checkpoint controlling Treg stability and IFN-γ—driven autoimmunity. Pharmacological stabilization of this interaction with 430C10 provides a proof-of-concept therapeutic strategy for restoring immune homeostasis in IPEX syndrome and related autoimmune diseases. Funding Source Our research is supported by National Natural Science Foundation of China (82271829, 32130041, 82441047, 82241222); The Innovation Program of Shanghai Municipal Education Commission (21140902900); Noncommunicable Chronic Diseases-National Science and Tech Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Regulatory T-cell (Treg) stability is maintained by dynamic remodeling of the FOXP3 transcriptional complex, and disruption of this complex leads to Treg dysfunction and immune dysregulation. However, how specific FOXP3 mutations alter the dynamic remodeling of the FOXP3 complex and thereby contribute to pathogenic Treg reprogramming in IPEX syndrome remains unclear. Here, we demonstrate that predominant Th1 inflammation manifests in both FOXP3V408M IPEX patients and FOXP3V408M knock-in mice and reveal that the mutation intrinsically impairs Treg-mediated control of Th1 inflammation, revealing a distinct pathogenesis of this mutation in IPEX syndrome. Mechanistically, the V408M mutation disrupts the FOXP3-T-bet interaction, impairing the FOXP3-mediated restraint of T-bet-driven IFN-γ production and thereby contributing to increased Th1 inflammation. Using an AI-driven virtual screening approach, we identified a first-in-class small molecule, FM029, that directly binds to FOXP3 and reinforces its interaction with T-bet. FM029 strongly suppressed Treg-derived IFN-γ production and alleviated IFN-γ-driven tissue inflammation in both FOXP3V408M mice and an acute colitis model. Collectively, these findings establish the FOXP3-T-bet interaction as a central checkpoint that governs Treg stability and IFN-γ-driven Th1 pathology, providing a proof-of-concept that pharmacologic stabilization of the FOXP3-T-bet interaction can mitigate IFN-γ-driven immune disorders.

BACKGROUND:Early-onset preeclampsia is characterized by maternal-fetal immune dysregulation and trophoblast dysfunction, commonly presenting with a reduction in regulatory T cells (Tregs) and impaired trophoblast invasion. However, the precise role of aberrant Treg-trophoblast communication in early-onset preeclampsia progression remains unclear. METHODS:A preeclampsia-like syndrome mouse model was established by administration of the nitric oxide inhibitor, NG-nitroarginine methyl ester hydrochloride. Mouse natural Tregs were adoptively transferred into the NG-nitroarginine methyl ester hydrochloride model via tail vein injection. Confirmatory experiments were conducted using an additional preeclampsia-like syndrome model generated by the administration of iMDK (MDK [midkine] and PI3K/Akt [the phosphatidylinositol 3-kinase/protein kinase B] inhibitor). An in vitro coculture model was established using a trophoblast cell line and human Tregs isolated from both umbilical cord/placental blood and maternal peripheral blood. RESULTS:Placentas from patients with early-onset preeclampsia had reduced numbers of Tregs compared with healthy controls. Adoptive Treg transfer activated the TβR1 (transforming growth factor β type I receptor)/Smad3 (Sma- and Mad-related protein 3) signaling pathway in trophoblasts, thereby enhancing their invasive and proliferative capacities and ultimately mitigating preeclampsia-like syndrome. Moreover, maternal peripheral blood MDK levels exhibited a significant inverse correlation with disease severity. MDK upregulates LAP (latency-associated peptide) expression on Tregs and acts synergistically with adoptive Treg transfer, resulting in a more pronounced therapeutic effect than Treg transfer alone. CONCLUSIONS:This study demonstrates that restoring Tregs ameliorates preeclampsia-like syndrome by enhancing trophoblast function. We further identify MDK as a key mediator enhancing this therapy, which upregulates LAP expression on Tregs and synergistically improves its overall efficacy against early-onset preeclampsia.

The tumor microenvironment (TME) plays a pivotal role in cancer progression, though the molecular regulators governing its immunosuppressive properties remain incompletely characterized. In this study, we identify Makorin-2 (MKRN2) as a novel modulator of TME remodeling through integrated analyses of genetically engineered mouse models and human clinical data. Utilizing MKRN2 knockout mice, we observed significantly accelerated tumor growth compared to wild-type control, which was associated with profound alterations in immune cell composition, especially M2 macrophages. Specifically, MKRN2 deficiency promoted a phenotypic switch in tumor-associated macrophages (TAMs) from anti-tumor M1 to pro-tumorigenic M2 polarization, with quantitative analysis revealing a 3-fold increase in the M2:M1 ratio. Clinical correlation studies demonstrated that MKRN2 expression was frequently downregulated across multiple human malignancies, with low MKRN2 levels strongly correlating with advanced disease stage and reduced patient survival. Mechanistic investigations revealed a dual regulatory mechanism of MKRN2 downregulation: epigenetic silencing through promoter CpG methylation and post-transcriptional suppression by oncogenic miR-582-5p. At the molecular level, MKRN2 functioned as an E3 ubiquitin ligase that directly targeted NF-κB p65 for proteasomal degradation, thereby constraining NF-κB/COX2-mediated inflammatory signaling. Reconstitution experiments demonstrated that MKRN2 overexpression significantly inhibited tumor cell proliferation, migration/invasion and tumor growth. Our findings establish MKRN2 as a critical regulator of immunosuppressive TME formation through coordinated control of macrophage polarization and NF-κB/COX2 signaling, suggesting its potential as both a prognostic biomarker and therapeutic target for cancer immunotherapy.

Systemic lupus erythematosus (SLE) is an autoimmune disease with unsatisfactory clinical outcomes. The abnormal B cell activation and pathogenic antibodies secretion are important in the pathogenesis of SLE. Bruton's tyrosine kinase (BTK) plays vital roles in B cell activation, development and differentiation. In this study, we investigated the inhibitory effect and mechanism of blocking BTK signaling in B cells as well as the therapeutic effect on SLE in mice. BTK gene knockout and its inhibitor ibrutinib were used to block BTK signaling. In vitro assays were conducted to explore the effects of blocking BTK expression on B cell responses. A mouse model of SLE was established, and the therapeutic effect of blocking BTK signaling on SLE was investigated. In vitro B cell culture and stimulation experiments demonstrated that blocking BTK signaling inhibited B cell activation, proliferation, differentiation, and antibody secretion. In vivo experiments revealed that blocking BTK significantly alleviates SLE and lupus nephritis. Furthermore, blocking BTK signaling reduced the levels of B, plasma, germinal center B, IgG-producing, and IgM-producing cells, and inhibited B cell development in SLE mice, as well as decreased the levels of pathogenic antibodies. Mechanistically, blocking BTK signaling inhibited B cell responses through suppressing PLCγ2 phosphorylation and its downstream pathways MYC, NFAT, and NF-κB. In conclusion, we demonstrated that Blocking BTK signaling inhibits B cell responses and antibody production, thereby alleviating SLE and lupus nephritis. Thus, BTK inhibitors are expected to be clinically used for treating SLE.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a potential contributor to RA pathogenesis. Methods: A systematic literature review was conducted to explore the mechanisms of ferroptosis in RA, focusing on iron metabolism dysregulation, oxidative stress, and immune cell dysfunction. Databases including PubMed, Embase, and Web of Science were searched for relevant studies. Results: RA patients exhibit paradoxical iron distribution, with systemic deficiency but synovial overload, promoting ferroptosis. Key findings include: (1) Iron accumulation and lipid peroxidation exacerbate synovial inflammation; (2) Ferroptosis differentially affects immune cells (M1/M2 macrophages, T cells) and fibroblast-like synoviocytes (FLS); (3) Antioxidant defenses (GPX4) are impaired in RA, while some disease-modifying drugs (leflunomide, sulfasalazine) may modulate ferroptosis. Conclusion: Ferroptosis plays a critical role in RA progression by disrupting synovial homeostasis. Targeting ferroptosis pathways offers promising therapeutic potential, though further research is needed to clarify cell-specific effects and optimize interventions.

Natural Killer (NK) cells have shown promising prospects in 'off-the-shelf' cell therapy, particularly the NK-92 cell line, which can serve as a foundation for the next generation of universal chimeric antigen receptor (CAR)-engineered NK products. A key strategy for generating universal cellular products is the elimination of the beta-2-microglobulin (B2M) gene, which encodes a component of MHC class I molecules (MHC-I) that plays a role in the presentation of foreign antigens and in the 'licensing' or 'education' of NK cells. To functionally study the impacts of MHC-I deficiency on NK-92, we generated a B2M knockout (KO) NK-92MI (B-92) cell line and compared the multidimensional properties of B2M KO and wild-type NK-92MI cells in terms of biological phenotypes, effector functions, and transcriptomic signatures. We observed a decrease in activating receptors, cytokine production, and cytotoxicity in B-92 cells. Further analysis of signalling events revealed that the upregulated expression and phosphorylation of SHP-1 in B-92 cells inhibited the phosphorylation levels of STAT3 and ERK, thereby affecting their killing function. By knocking out SHP-1 (PTPN6), we partially restored the cytotoxic function of B-92 cells. Notably, we also found that CAR modification can overcome the hyporesponsiveness of B-92 cells. These findings will facilitate further exploration in the development of NK cell-based products.

The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).

Behçet's uveitis (BU), characterized by recurrent bilateral panuveitis, is a severe manifestation of Behcet's disease (BD). However, disease-specific metabolic alterations in BU remain largely unknown. Here, untargeted metabolomics and single-cell RNA sequencing (scRNA-seq) are performed in patients with BU and healthy controls (HC). scRNA-seq data of experimental autoimmune uveitis (EAU) mice are also incorporated. The data showed an altered metabolic profile, characterized by upregulated glycolysis in BU. MYC is predicted to be a hub molecule regulating glycolysis and T cell response. Notably, it is discovered that the expression level of MYC is higher in BU compare to HC and may reflect the treatment response of BU disease. Correspondingly, the scRNA-seq data of EAU mice also reveal higher glycolysis levels and MYC expression. Further studies reveal that inhibition of MYC repressed glycolysis and exerted therapeutic effects similar to those of glycolysis inhibitors, including amelioration of EAU and repression of the abnormal response of effector T cells (T helper [Th]-1 and Th17 cells). Mechanically, inhibiting MYC disrupts the glycolysis-PI3K signaling circuit to curb the effector T cell response in uveitis. Collectively, the study indicated that MYC promoted glycolysis to fuel abnormal T-cell responses, thus therapeutically targeting MYC would provide an attractive approach for treating BU.

Atherosclerosis remains the primary driver of cardiovascular and cerebrovascular morbidity and mortality. A pivotal event in its pathogenesis is the phenotypic conversion of vascular smooth muscle cells (VSMCs), particularly the transition from a contractile to a macrophage-like state. Using a murine model of atherosclerosis, we demonstrate that this process is orchestrated by a progressively disrupted perivascular immune milieu characterized by an expansion of CD44⁺ memory CD4⁺ T cells at the expense of CD44- naive CD4⁺ T cells. Within this niche, CD44⁺ natural regulatory T cells (nTregs) actively promote VSMCs macrophage-like reprogramming, whereas their CD44- counterparts exert an opposing, protective effect. Reciprocally, macrophage-like VSMCs foster the trans-differentiation of nTregs into pathogenic Th17 cells, amplifying vascular inflammation. In contrast, induced Treg cells (iTregs) display phenotypic stability and potently inhibit VSMCs macrophage-like switching, restrict pathological VSMCs migration, and curtail VSMCs survival. Systemic infusion of iTregs selectively remodels the perivascular immune microenvironment toward an antiatherogenic profile. Adoptive transfer of iTregs at early disease stages decreased the abundance of macrophage-like VSMCs, attenuated plaque burden, and these benefits were partially mediated by transforming growth factor β signaling. Collectively, iTreg-based cellular therapy represents a promising strategy to intercept VSMCs macrophage-like transformation and limit atherosclerotic progression.