We use mathematical modeling to study the proliferation dynamics of CD4+ T cells within an immune response. This proliferation is driven by the autocrine reaction of helper T cells and interleukin-2 (IL-2), and regulated by natural regulatory T cells (nTregs). Previous studies suggested that a fratricidal mechanism is necessary to eliminate helper T cells post-infection. Contrary to this, our mathematical analysis establishes that the depletion of these cells is due to two pivotal factors: the saturation in the proliferation rate of helper CD4+ T cells at high IL-2 concentrations, and the activation rate of nTregs outpacing their death rate. This yields an excitable process, such that the proliferation starts once the helper T cell population passes a threshold. Additionally, we find that when the proliferation of nTregs lags behind their mortality, induced regulatory T cells (iTregs) are crucial to curbing the proliferation of helper CD4+ T cells.

Despite extensive research on immune activation regulatory mechanisms, studies on immune suppression in psoriasis are limited. LAG3, a newly identified immune checkpoint, plays a crucial role in modulating immune responses and maintaining T-regulatory cell function. However, its involvement in psoriasis is unclear. We show that psoriasis is associated with reduced LAG3 expression in CD4 T cells and T-regulatory cells. Further analysis revealed that the decline in LAG3 levels was linked to ADAM10/17-mediated proteolytic cleavage, which was upregulated in psoriasis. Clinical utilization of the IL-17A antagonist secukinumab, along with the in vivo and in vitro IL-17A-induced models, supported the potential of IL-17A to induce ADAM10/17 expression and trigger LAG3 cleavage. Through the Jurkat cell model, IL-17A was found to regulate ADAM10/17 expression by activating FOXM1. In addition, treatment with the ADAM10/17 inhibitor GW280264X showed ameliorative effects on psoriasis-like mouse models and lipopolysaccharide-induced inflammation. Collectively, the findings of this study uncover the immune regulatory role of the ADAM10/17-LAG3 axis in psoriasis and highlight the therapeutic potential of targeting ADAM10/17 for psoriasis treatment.

Biomaterial implants are a critical aspect of our medical therapies and biomedical research and come in various forms: stents, implantable glucose sensors, orthopedic implants, silicone implants, drug delivery systems, and tissue engineered scaffolds. Their implantation triggers a series of biological responses that often times lead to the foreign body response and subsequent fibrotic encapsulation, a dense ECM-rich capsule that isolates the biomaterial and renders it ineffective. These responses lead to the failure of biomaterials and is a major hurdle to overcome and in promoting their success. Much attention has been given to macrophage populations for the inflammatory component of these responses to biomaterials but recent work has identified an important role of T cells and their ability to modulate fibroblast activity and vice versa. In this review, we focus on T cell-fibroblast crosstalk by exploring T cell subsets, critical signaling pathways, and fibroblast populations that have been shown to dictate biomaterial-mediated fibrosis. We then highlight emerging technologies and model systems that enable new insights and avenues to T cell-fibroblast crosstalk that will improve biomaterial outcomes.

The purpose of this study is to assess the potential causal relationship between immune cell phenotype and oral cancer using Mendelian randomisation analysis.

A two-sample Mendelian randomisation (MR) analysis using summary statistics from genome-wide association studies in European populations was conducted to explore causal relationships between immune cell phenotypes and the risk of oral cancer. Inverse-variance weighting, MR-EGGER, simple mode, weighted median, and weighted mode were applied for MR analysis. Sensitivity analyses, including the Steiger test, Cochran's Q test, Egger intercept, and leave-one-out analysis, were performed to assess the robustness of the results. Additionally, colocalisation analysis was carried out to further validate causal associations.

A total of 21 immune cell phenotypes were identified as risk factors for oral cancer, while 6 immune cell phenotypes demonstrated protective effects. Sensitivity analyses indicated a lack of robustness in four causal relationships. Genetic variants at rs9469077 on chr6 might be shared between CD28-CD127-CD25++CD8br AC of regulatory T cells and oral cancer.

This MR study provides evidence for a strong association between immune cells and oral cancer, highlighting specific immune cell phenotypes as significant risk factors for the development of oral cancer. These findings offer a foundation for future precision immunotherapy strategies for oral cancer. Further studies are required to confirm the relationship between immune cells and oral cancer risk and to elucidate the underlying mechanisms.

This study confirms the potential relationship between specific immune cell phenotypes and oral cancer, providing theoretical support for future immunotherapy against oral cancer.

Sepsis is a life-threatening complication caused by the overwhelming immune response to bacterial infection leading to the fatal organ damage and even death. Helminth infections modulate host's immune system through secreting functional proteins to reduce host immune attack as a survival strategy, therefore have been used for the therapy of some inflammatory or autoimmune diseases. Sj-Cys is a cysteine protease inhibitor secreted by Schistosoma japonicum exerting strong immunomodulatory function which has been used to treat sepsis, however, the mechanism underlying the therapeutic efficacy has not been fully elucidated. In this study, we expressed Sj-Cys as recombinant protein (rSj-Cys) in prokaryotic system and rSj-Cys was used to incubate with mouse bone marrow derived dendritic cells (BMDCs) in vitro. Our study revealed that rSj-Cys was able to induce differentiation of BMDCs to tolerant property (TolDCs). Adoptive transfer of rSj-Cys induced-TolDCs into mice with cecal ligation and puncture (CLP)-induced sepsis conferred a significant therapeutic effect on CLP-induced sepsis in mice with reduced mortality and vital organ damage. The therapeutic effect of Sj-Cys-induced TolDCs was associated with upregulation of CD3+CD4+CD25+Foxp3+ regulatory T cells (Tregs) and reduced inflammatory cytokines IL-6 and TNF-α and boosted level of regulatory cytokines IL-10 and TGF-β. The results identified in this study further suggest rSj-Cys has the potential to be developed into a drug substance for the treatment of inflammatory or autoimmune diseases due to its immunomodulatory effect on tolerant dendritic cells and regulatory T cells.

Mitochondrial diseases (MtD) provide a unique window into the complex interplay between metabolism and immune function. These rare disorders, caused by defects in oxidative phosphorylation, result in bioenergetic deficiencies that disrupt multiple organ systems. While traditionally studied for their metabolic impact, MtD also profoundly affect the immune system, altering both innate and adaptive responses. This review explores how mitochondrial dysfunction shapes immune dysregulation, influencing thymocyte maturation, regulatory T cells, and B cell function while also driving innate immune activation through mitochondrial DNA instability and type I interferon signaling. Additionally, MtD highlight an emerging overlap between inborn errors of metabolism and inborn errors of immunity, revealing shared pathways that connect mitochondrial dysfunction to immune deficiencies and inflammatory disease. Studying MtD not only advances our understanding of immunometabolism but also provides critical insights into more common inflammatory and autoimmune conditions, offering potential therapeutic targets that extend beyond rare mitochondrial disorders.

Metabolic reprogramming plays an important role in therapeutic efficacy of hepatocellular carcinoma (HCC). However, the metabolic reprogramming-related key genes associated with transcatheter arterial chemoembolization (TACE) treatment sensitivity in HCC remain further investigation.

We analyzed data from public databases, The Cancer Genome Atlas and Gene Expression Omnibus, as well as metabolism-related genes (MRGs), to identify key genes associated with TACE treatment sensitivity. Further analysis was conducted on the relationship between key genes and immune cell infiltration, HCC-related genes, regulatory network construction, nomogram construction, and drug sensitivity analysis. Finally, the expression of key genes was validated based on databases and in vitro RT-qPCR.

Four key genes (CDC20, LPCAT1, PON1, and SPP1) associated with TACE treatment sensitivity were identified. Increased CDC20, LPCAT1, and SPP1 and reduced PON1 were found in tumor tissues than normal tissues, as well as in advanced patients than early-stage patients. Lower expression of CDC20, LPCAT1, and SPP1, and higher expression of PON1 were detected in responsive patients than non-responsive patients. Patients with high expression of CDC20, LPCAT1, and SPP1, and low expression of PON1 had poor prognosis. They were also correlated with tumor immune microenvironment and sensitivity to multiple chemotherapy drugs. The expressions of key genes at the gene and protein levels were validated.

Our study provided systematic insights into identification of biomarkers for TACE treatment sensitivity in HCC.

Aberrant interaction between innate immune and adaptive immune cells can disrupt tissue homeostasis, consequently triggering chronic inflammatory diseases such as rheumatoid arthritis (RA) and periodontitis (PD). Pro-inflammatory macrophages serve as critical mediators in the early immune response, constituting a major population of CD80+ cells, while anti-inflammatory macrophages modulating inflammatory processes through the secretion of transforming growth factor-beta (TGF-β). This cytokine facilitates the differentiation of peripheral regulatory T cells (Tregs) and contributes to the establishment of immune tolerance. However, there are no definitive therapies to reshape the tissue homeostasis between innate immune and adaptive immune cells.

(1) anti-CD80-MTX-EVs was obtained by gradient centrifugation, which were characterized by TEM and DLS, and the associated membrane proteins were identified by Western Blot. (2) The mouse bone marrow-derived macrophages were co-cultured separately with EVs, anti-CD80-EVs, and anti-CD80-MTX-EVs in vitro, and the expression of CD80 on the macrophages surface as well as the proportion of Treg cell generation were detected. (3) EVs, anti-CD80-EVs and anti-CD80-MTX-EVs were injected into mice models of arthritis and periodontitis for treatment, the therapeutic effect was evaluated by the expressions of related cytokines, staining of HE, the proportion of CD80+ macrophages and the phenotypic differentiation of T cells in the tissues.

We successfully constructed engineered EVs (anti-CD80-MTX-EVs) targeting inflammatory macrophages for intracellular MTX delivering, which inducing the anti-inflammatory transformation while upregulating the expression of TGF-β of macrophages. Furthermore, our findings demonstrate that anti-CD80-MTX-EVs effectively reduce CD80+ macrophage levels, promote Treg cell generation, and inhibit Th1 cell production in vivo.

In this study, the anti-CD80-MTX-Evs demonstrated significant therapeutic effects in both rheumatoid arthritis and periodontitis models through a triple mechanism: reducing CD80+ macrophage population, enhancing Treg cell differentiation, and suppressing Th1 cell development. Overall, this study presents an innovative strategy for resolving inflammation within chronic inflammatory diseases.

Islet transplantation is a promising therapy for insulin-dependent diabetes. However, immune rejection and insufficient vascularization hinder the survival and function of transplanted islets. Here, we show effective engraftment of vascularized and functional mouse and rat islets transplanted into biomaterial-remodeled spleens of nonimmunosuppressed rodents and human islets transplanted into the remodeled spleens of nonhuman primates (NHPs) on varying degrees of immunosuppression. We found evidence that konjac glucomannan-modified silica nanoparticles (KSiNPs) remodeled the spleen into an extracellular matrix (ECM)-rich, immunosuppressive niche to support the survival of syngeneic or xenogeneic islets. Transplanted islets in the remodeled spleens showed improved engraftment, neovascularization, and functionality and restored normoglycemia in streptozotocin (STZ)-induced type 1 diabetic models in the mice and macaques, with stable insulin and C-peptide secretion in mice for 90 days and macaques for 28 days. KSiNP injection and islet transplantation into macaque spleens under B-ultrasound guidance were preclinically feasible. These findings highlight the safety and effectiveness of spleen tissue remodeling in supporting the survival and function of transplanted islets, providing a promising strategy for treating type 1 diabetes mellitus (T1DM).

Dendritic cells (DCs) are critical regulators of immune homeostasis, balancing tolerance and immunity through antigen presentation and T cell modulation. While the influence of hypoxia (<2% O2) on DC function in pathological settings is well-documented, the impact of physiological O2 levels remains underexplored. This study investigates the role of physioxia (4% O2) in programming mature DCs toward a tolerogenic phenotype compared to atmospheric conditions (21% O2) typically present in in vitro assays. DC cultures generated under 4% O2 exhibited a reduced monocyte-to-DC transformation rate, increased lactate production, a semi-mature surface marker profile, and increased surface expression of the tolerance-associated marker ILT4. T cell priming was altered only when atmospheric DCs were co-cultured under physioxia, suggesting an O2-dependent threshold for immunostimulatory capacity. These findings highlight the complexity of O2-dependent mechanisms in DC-T cell interactions, revealing a delicate balance between tolerance and immunogenicity. Our results underscore the need for physiologically relevant O2 conditions in DC research to better reflect in vivo behavior and inform immunotherapy design. Overall, this study advances understanding of how microenvironmental cues shape DC biology, with implications for immune tolerance, autoimmunity, and cancer immunotherapy.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia, skin inflammation, and immune dysregulation. These factors contribute to the persistent progression of the disease. While addressing excessive keratinocyte proliferation or inhibiting inflammation may provide temporary therapeutic relief, unresolved immune dysregulation often exacerbates the condition. Therefore, comprehensive treatments that alleviate skin symptoms and regulate immune tolerance are urgently required. An ideal treatment would target multiple factors, including keratinocyte proliferation, inflammation, and immune tolerance, while minimizing systemic side effects. In this study, we developed a dissolvable hyaluronic acid microneedle patch containing regulatory T cell (Treg) exosomes loaded with dimethyl fumarate (DMF) (rExo@DMF MNs). DMF acts as an inhibitor of keratinocyte proliferation and an anti-inflammatory agent through NF-κB suppression and Nrf2 activation, inhibiting the production of pro-inflammatory cytokines and the activation of inflammatory cells. Delivering DMF via Treg exosomes enhances its retention at the lesion site. This system inhibits keratinocyte proliferation and migration, reduces pro-inflammatory cytokine release, and alleviates epidermal hyperplasia and inflammation in an imiquimod-induced psoriasis mouse model. Additionally, Treg exosomes modulate immune responses to promote tolerance. rExo@DMF MNs demonstrate immunomodulatory effects by inhibiting T helper 17 (Th17) cells and inducing regulatory immune cells such as Tregs and tolerogenic dendritic cells (tDCs) differentiation. rExo@DMF MNs alleviate skin symptoms and regulate immune cells in the skin, spleen, and lymph nodes, demonstrating both local and systemic immunoregulation with promising therapeutic potential for psoriasis. STATEMENT OF SIGNIFICANCE: Novel therapies are urgently needed to alleviate skin symptoms and regulate immunity, as current psoriasis treatments focus on symptom relief while neglecting the underlying immune dysfunction, resulting in limited efficacy. Moreover, systemic immunosuppression often leads to severe side effects. This study introduces a hybrid microneedle system (rExo@DMF MNs) that alleviates psoriasis symptoms and modulates immune responses locally and systemically. In addition, rExo@DMF MNs penetrate hyperkeratotic skin, ensuring targeted rExo@DMF release while minimizing systemic exposure and side effects. All components of the system, including hyaluronic acid (a key component of the skin matrix), regulatory T cell-derived exosomes, and DMF (a clinically validated drug), exhibit biocompatibility. This comprehensive approach addresses multiple pathogenic factors, promising an effective and safe psoriasis treatment.

Regulatory T cells (Tregs), previously referred to as suppressor T cells, represent a distinct subset of CD4+ T cells that are uniquely specialized for immune suppression. They are characterized by the constitutive expression of the transcription factor FoxP3 in their nuclei, along with CD25 (the IL-2 receptor α-chain) and CTLA-4 on their cell surface. Tregs not only restrict natural killer cell-mediated cytotoxicity but also inhibit the proliferation of CD4+ and CD8+ T-cells and suppress interferon-γ secretion by immune cells, ultimately impairing an effective antitumor immune response. Treg cells are widely recognized as a significant barrier to the effectiveness of tumor immunotherapy in clinical settings. Extensive research has consistently shown that Treg cells play a pivotal role in facilitating tumor initiation and progression. Conversely, the depletion of Treg cells has been linked to a marked delay in tumor growth and development.

Celiac disease (CeD), triggered by gliadin exposure, necessitates therapeutic strategies that establish an antigen-specific immune tolerance. This study explores the therapeutic efficacy and mechanism of rapamycin-gliadin composite nanoparticles (PLN-GR) for CeD treatment. In vivo analyses demonstrated the efficient uptake of PLN-GR by antigen-presenting cells (APCs), particularly Kupffer cells and splenic dendritic cells (DCs), driving their tolerogenic phenotypic transformation. In a murine CeD model, PLN-GR administration significantly enhanced gluten tolerance and mitigated intestinal inflammation, as indicated by reduced paw edema and improved histopathological parameters. Mechanistically, PLN-GR induced macrophage metabolic reprogramming from glycolysis to oxidative phosphorylation, concomitant with elevated serum itaconate levels. This metabolic shift potentiated interorgan immunoregulatory crosstalk, expanding PD-L1+ tolerogenic splenic DCs while suppressing pathogenic Th1 cell populations. Bone marrow-derived macrophages (BMDMs) from Acod1-/- mice (deficient in itaconate synthesis) failed to induce DC tolerance upon PLN-GR treatment. However, supplementation with the itaconate derivative 4-octyl itaconate (4-OI) restored PD-L1 expression in DC2.4 cells in vitro, revealing that itaconate induces and stabilizes the tolerant DC phenotype. These findings underscore PLN-GR as a novel nanotherapeutic platform for CeD, achieving gliadin-specific tolerance through hepatic-splenic immunometabolic reprogramming and itaconate-dependent PD-L1 regulation, thereby offering a translatable strategy for autoimmune disease management.

The regulation of immune responses to promote tolerance to the fetus is critical for successful pregnancy. An understudied aspect of this process is the initiation of regulation pre-conception via exposure to semen. Our study aimed to understand how semen impacts recipient dendritic cells (DCs) and their subsequent role in shaping CD4 T cell differentiation.

Monocyte-derived DCs (MoDCs) were exposed to semen extracellular vesicles (SEV) or vesicle-depleted semen plasma (VDSP). Phenotypic and functional markers were analyzed using flow cytometry. We also exposed epithelial sheets from vaginal tissue to SEV and VDSP, and measured the number and marker expression of emigrating cells. Finally, we tested how SEV- or VDSP-exposed DCs altered CD4 T cell differentiation by co-culturing exposed MoDCs or tissue emigrated cells with autologous naïve CD4 T cells.

MoDCs exhibited a significant increase of CD141, CD1a, CD38, and ILT4 expression when exposed to SEV or VDSP. A unique feature of semen-treated MoDCs was expression of indoleamine 2,3-dioxygenase (IDO), a potent contributor to the induction of regulatory T cells (Tregs). SEV but not VDSP significantly increased the emigration of intraepithelial DCs. Additionally, SEV significantly enhanced the expression of multiple immunoregulatory markers in the emigrated DCs. After co-culture, we observed significantly more FOXP3+ Tregs expressing high levels of TIGIT in the groups that were initially exposed to SEV.

These findings indicate that exposure to SEV induces a tolerogenic program in DCs that can direct differentiation of a unique memory Treg subset, primed for expansion and presumably destined to support a successful pregnancy.

This study explored the immunomodulatory effects of Rehmanniae Radix Praeparata polysaccharides (RP) on LPS-induced immune activation. RP, characterized as a heteropolysaccharide (6.34 kDa and 4.63 kDa) rich in galactose and glucose, was administered to LPS-challenged BALB/c mice at 25 mg/kg and 50 mg/kg doses. Results showed RP significantly reduced pro-inflammatory cytokines (TNF-α, IL-6), lowered oxidative stress (MDA), and boosted antioxidant enzymes (SOD, GSH-Px). It restored splenic structure, mitigated apoptosis, and suppressed the TNF-α/NF-κB/IL-6 pathway. Metabolomics linked RP to sphingolipid metabolism, while gut microbiota analysis revealed increased beneficial bacteria and elevated SCFAs. Transcriptomics confirmed RP's immune regulation via TNF signaling. These findings demonstrate RP's potential in alleviating immune overactivation by modulating inflammation, gut microbiota, and SCFA production, suggesting therapeutic promise for immune-related diseases.

Vaccines have been proven to be one of the safest and most effective ways to prevent and combat diseases. However, the main focus has been on the evaluation of the potency of effector mechanisms and the lack of adverse effects of vaccine candidates. Recently, the importance of induced regulatory mechanisms of the immune system after vaccination has come to light. With the increase in our knowledge about these regulatory mechanisms including the regulatory T cells (Tregs), we have come to understand the significance of this arm of the immune system in controlling immunopathology and/or diminishing the effectiveness of vaccines, especially viral vaccines. Tregs play a dual role during infectious diseases by limiting immune-mediated pathology and also contributing to chronic pathogen persistence by decreasing effector immunity and clearance of infection. Tregs may also affect immune responses after vaccination primarily by inhibiting antigen presenting cell function such as cytokine secretion and co-stimulatory molecule expression as well as effector T (Teff) and B cell function. In this article, we review the current knowledge on the induction of Tregs after several life-threatening virus infections and their available vaccines to bring them to the spotlight and emphasise that studying viral-induced antigen-specific Tregs will help us improve the effectiveness and decrease the immunopathology or side effects of viral vaccines. Trial Registration: ClinicalTrials.gov identifier: NCT04357444.

Introduction: Expression of P16ink4A and FOXP3 is correlated with the grades of cervical lesions. In this study, we determined the diagnostic accuracy of serum P16ink4A and FOXP3 concentrations for detection of cervical intraepithelial neoplasia (CIN) and cervical cancer (CC) in a rural setting in Southwestern Uganda. Material and Methods: CIN and CC cases (93 each before treatment), and 93 controls were identified. Clinical and demographic data were documented before quantifying serum P16ink4A and FOXP3 concentrations using quantitative ELISA kits. Cases were confirmed by cytology and/or histology. We employed descriptive statistics, cross-tabulation, and receiver operating curves (ROC) using statistical software for data science (STATA) 17. p-values <0.05 were considered statistically significant. Results: Serum FOXP3 concentration of 0.0545 ng/mL < showed moderate sensitivity (32.22% and 57.78%) for detection of CIN and CC from healthy controls, respectively. It also showed a moderately high specificity of 68.89% for detection of both CIN and CC from healthy controls (AUC-0.6014 and 0.7679, respectively). Serum P16ink4A concentration of 0.946 ng/mL < showed moderate sensitivities (50.00% and 60.00%) and specificities (56.67% and 55.56%) for the detection of CIN and CC from healthy controls, respectively (AUC-0.6085 and 0.7592, respectively). A combination of elevated serum FOXP3 and P16ink4A showed very low sensitivities of 18.89% in detecting CIN from healthy controls and 33.33% for detecting CC from healthy controls. This combination showed high specificity of 83.33% in detecting both CIN and CC from healthy controls (AUC-0.5992 and 0.7642, respectively). Conclusion: Although serum P16ink4A and FOXP3 concentrations showed moderate accuracy, their combination was more specific than sensitive. This combination has a high potential to be applied for diagnosis rather than screening for cervical lesions, at least in the Ugandan population. Combinations of P16ink4A and FOXP3 with other biomarkers could improve diagnostic accuracies. Additionally, studies could be conducted to assess the performance of these biomarkers in the detection of cervical lesions in specific populations, say Human Immunodeficiency Virus (HIV)-positive and HIV-negative populations.

The oral delivery of DNA/RNA nanoparticles represents a transformative approach in immunotherapy and vaccine development. These nanoparticles enable targeted immune modulation by delivering genetic material to specific cells in the gut-associated immune system, triggering both mucosal and systemic immune responses. Unlike parenteral administration, the oral route offers a unique immunological environment that supports both tolerance and activation, depending on the formulation design. This review explores the underlying mechanisms of immune modulation by DNA/RNA nanoparticles, their design and delivery strategies, and recent advances in their application. Emphasis is placed on strategies to overcome physiological barriers such as acidic pH, enzymatic degradation, mucus entrapment, and epithelial tight junctions. Special attention is given to the role of gut-associated lymphoid tissue in mediating immune responses and the therapeutic potential of these systems in oral vaccine platforms, food allergies, autoimmune diseases, and chronic inflammation. Despite challenges, recent advances in nanoparticle formulation support the translation of these technologies into clinical applications for both therapeutic immunomodulation and vaccination.

Adult T-cell leukemia-lymphoma (ATL) is one of the most severe malignant T-cell leukemia/lymphomas induced by human T-cell leukemia virus type I (HTLV-1). HTLV-1 persists in the host through stratagems of proliferating infected cells and evading host immunity. HTLV-1 encodes two viral oncogenes, tax and HTLV-1 bZIP factor (HBZ), which are related with protection from cell death and promotion of cell proliferation. In addition, HBZ and the somatic mutations in host genes, such as C-C chemokine receptor 4 (CCR4) and CIC, convert HTLV-1-infected cells into regulatory T (Treg)-like cells, leading to evasion of host immunity. A recent study demonstrated the key mechanisms for clonal expansion of HTLV-1-infected cells; the activation of the transforming growth factor (TGF)-β signaling pathway by HBZ not only converts HTLV-1-infected cells into a Treg-like cells through Foxp3 expression, but also contributes to the proliferation of HTLV-1-infected cells themselves. Due to the longevity induced by HTLV-1 infection, somatic mutations and epigenetic aberrations are accumulated in infected clones, contributing to the oncogenesis of ATL. Collectively, the long-term survival of infected cells enabled by the HTLV-1's stratagems for persistent infection ultimately leads to ATL oncogenesis via the accumulation of genetic/epigenetic abnormalities.

We explore the interaction between corneal immunity and mesenchymal stem/stromal cells (MSCs) and their potential in treating corneal and ocular surface disorders. We outline the cornea's immune privilege mechanisms and the immunomodulatory substances involved. In this realm, MSCs are characterized by their immunomodulatory properties and regenerative potential, making them promising for therapeutic application. Therefore, we focus on the role of MSCs in immune-mediated corneal diseases such as dry eye disease, corneal transplantation rejection, limbal stem cell deficiency, and ocular graft-versus-host disease. Preclinical and clinical studies demonstrate MSCs' efficacy in promoting corneal healing and reducing inflammation in these conditions. Overall, we emphasize the potential of MSCs as innovative therapies in ophthalmology, offering promising solutions for managing various ocular surface pathologies.

Cancer stem cells (CSCs) are a distinct subpopulation of cancer cells with the capacity to constantly self-renew and differentiate, and they are the main driver in the progression of cancer resistance and relapse. The tumor microenvironment (TME) constructed by CSCs is the "soil" adapted to tumor growth, helping CSCs evade immune killing, enhance their chemical resistance, and promote cancer progression.

We aim to elaborate the tight connection between CSCs and immunosuppressive components of the TME. We attempt to summarize and provide a therapeutic strategy to eradicate CSCs based on the destruction of the tumor ecological niche.

This review is focused on three main key concepts. First, we highlight that CSCs recruit and transform normal cells to construct the TME, which further provides ecological niche support for CSCs. Second, we describe the main characteristics of the immunosuppressive components of the TME, targeting strategies and summarize the progress of corresponding drugs in clinical trials. Third, we explore the multilevel insights of the TME to serve as an ecological niche for CSCs.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent disorder of excessive fat accumulation and inflammation in the liver that currently lacks effective therapeutic interventions. Fu brick tea (FBT) has been shown to ameliorate liver damage and modulate gut microbiota dysbiosis in NAFLD, but the potential mechanisms have not been comprehensively elucidated, especailly whether its hepatoprotective effects are determined to depend on the homeostasis of gut microbiota, intestinal barrier function and hepatic immune microenvironment. In this study, our results further demonstrated that FBT not only alleviated NAFLD symptoms and related endotoxemia in high-fat diet (HFD)-fed rats, but also attenuated intestinal barrier dysfunction and associated inflammation, also confirmed in Caco-2 cell experiment. Meanwhile, FBT intervention significantly relieved HFD-induced gut microbiota dysbiosis, characterized by increased diversity and composition, particularly facilitating beneficial microbes, including short chain fatty acids (SCFAs) and bile acids producers, such as Blautia and Fusicatenibacter, and inhibiting Gram-negative bacteria, such as Prevotella_9 and Phascolarctobacterium. Also, the gut microbiota-dependent hepatoprotective effects of FBT were verified by fecal microbiota transplantation (FMT) experiment. Thus, the beneficial moulation of gut microbiota altered by FBT in levels of SCFAs, bile acids and lipopolysaccharides, intestinal barrier function and TLR4/NF-κB pathway contributed to alleviate liver steatosis and inflammation. Additionally, the hepatoprotective effects of FBT was further demonstrated by suppressing Kupffer cell activation and regulating lipid metabolism using an ex vivo model of liver organoid. Therefore, FBT supplementation can maintain intenstinal homeostasis and remodel hepatic immune microenvironment to prevent NAFLD and associated endotoxemia.

Recent studies using single-cell RNA sequencing technology have uncovered several subpopulations of CD4+ T cells that accumulate with aging. These age-associated T cells are emerging as relevant players in the onset of inflammaging and tissue senescence. Here, based on information provided by single-cell RNA sequencing data, we present a flow cytometry panel that allows the identification of age-associated T cell subsets in systematic larger analysis in mice. We use this panel to evaluate at the single-cell level mitochondrial and senescence marks in the different age-associated CD4+ T cell subpopulations. Our analysis identifies a subpopulation of regulatory T (Treg) cells that is characterized by the extracellular expression of the co-inhibitory molecule killer cell lectin-like receptor subfamily G member 1 (KLRG1) and accumulates with aging in humans and mice. KLRG1-expressing Treg cells display senescence features such as mitochondrial alterations, increased expression of cell-cycle regulators and genomic DNA damage. Functionally, KLRG1+ Treg cells show a reduced suppressive activity in vivo accompanied by a pro-inflammatory phenotype.

The prevalence of allergic diseases has been rising, paralleling lifestyle changes and environmental exposures that have altered human microbiome composition. This review article examines the intricate relationship between the gut microbiome and allergic diseases, emphasizing the potential of fecal microbiota transplantation as a promising novel treatment approach. It explains how reduced microbial exposure in modern societies contributes to immune dysregulation and the increasing incidence of allergies. The discussion also addresses immune homeostasis and its modulation by the gut microbiome, highlighting the shift from eubiosis to dysbiosis in allergic conditions. Furthermore, this article reviews existing studies and emerging research on the role of fecal microbiota transplantation in restoring microbial balance, providing insights into its mechanisms, efficacy, and safety.

Lichen sclerosus (LS) is a chronic inflammatory skin disorder primarily affecting the anogenital region, leading to symptoms such as itching, pain, and sexual dysfunction, all of which significantly impact patients' quality of life. Due to the non-specific nature of its early symptoms, diagnosis is often delayed. This review examines the cytokine networks involved in LS, with a focus on immune activation, the role of T-helper (Th)1 cells, and the interaction between inflammatory mediators and the extracellular matrix, particularly in fibrosis. By providing an updated understanding of LS immunopathogenesis, this review highlights key mediators involved in disease progression and offers insights into personalized treatment strategies that may improve patient outcomes. Additionally, current therapeutic approaches and future directions in LS management are discussed.

Autoimmune diseases including rheumatoid arthritis (RA) are often associated with high levels of reactive oxygen species (ROS); however, the ROS targets in autoimmunity are diverse and unclear. Using collagen-induced arthritis (CIA) mice as a model for RA, we report that antioxidants markedly suppress joint inflammation, antibody production, and effector T cell responses. We found that the frequency of CD4+ regulatory T cells (Tregs) was reduced in CIA mice, which was reversed by antioxidant treatment, and SOCS3, known to be associated with Treg instability, was upregulated in Tregs from both RA patients and CIA mice. Mechanistically, SOCS3 upregulation was induced by ROS-dependent PTEN oxidation and the resultant Akt/mTOR/STAT3 activation. We further showed that the source of ROS involved in this pathway is NADPH oxidase 2 (Nox2). Nox2 expression was upregulated in Tregs from CIA mice, and Nox2 transduction induced a decrease in Treg frequency that depended on SOCS3 upregulation. This study thus provides a mechanistic understanding of ROS-induced Treg instability and suggests that ROS-dependent disruption of Treg homeostasis underlies the development and progression of autoimmune diseases.

Does the restoration of regulatory T cells (Tregs) suppress the progression of endometriosis?

Adoptive transfer of Tregs suppresses the progression of endometriosis and reduces the levels of helper T (Th)-cell-related and proinflammatory cytokines in mice.

Endometriosis is a chronic inflammatory gynecological disease, which involves multiple immune components. Activated Treg counts decrease in the endometrioma and endometrium of patients with endometriosis, and depletion of Tregs exacerbates endometriosis in mice.

We evaluated the effects of adoptive transfer of Tregs on the progression of endometriosis in mice. We used Foxp3tm3Ayr/J (Foxp3DTR) mice with temporarily ablated Tregs by injecting diphtheria toxin to develop an endometriosis model, which was generated by ovariectomy, estradiol administration and transplantation of uterine fragments from donor mice. Foxp3DTR mice were randomly divided into Treg adoptive transfer (n = 12) and control (n = 11) groups. Tregs were isolated from lymph nodes and spleens of wild-type (WT) mice and were adoptively transferred into mice that were temporarily Treg-depleted. Control mice were injected with vehicle. Treg adoptive transfer was performed on the day of uterine implantation, and a second adoptive transfer was performed after 14 days. Mice were euthanized 28 days after uterine implantation, and blood, peritoneal fluid, spleen, and endometriosis-like lesion samples were collected.

Foxp3DTR mice were intravenously injected with Tregs isolated from WT mice. The number, total weight, and total volume of the endometriosis-like lesions were evaluated on Day 28 following implantation of uterine fragments. The proportion of Tregs in endometriosis-like lesions, ascites, and peripheral blood was analyzed by flow cytometry. Inflammation in lesions and serum was examined using real-time PCR and ELISA.

Injection of Tregs increased their total count and decreased the number (P < 0.0001), weight (P = 0.0021), and volume (P = 0.0010) of endometriosis-like lesions in Foxp3DTR Treg-depleted mice. Furthermore, injection of Tregs decreased the mRNA expression of Th 1-, 2-, and 17-related cytokines, including interferon gamma (P = 0.0101), interleukin (IL)-4 (P = 0.0051), and IL-17 (P = 0.0177), as well as the levels of the proinflammatory cytokine IL-6 (P = 0.0002), in endometriosis-like lesions of Foxp3DTR Treg-depleted mice.

N/A.

Treg-related immune mechanisms in mice may not precisely reflect those in humans.

Restoration of Tregs may be a useful therapeutic strategy for inhibiting the progression of endometriosis in cases where the decrease in the Treg population is an exacerbating factor.

This study was partially supported by the Grants-in-Aid for Scientific Research (grant numbers 18K16808 and 20K22983) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The sponsor had no role in the study design, collection, analysis and interpretation of data, writing of the report, and decision to submit the article for publication. The authors have no conflicts of interest to disclose.

Osteoporosis is the most common skeletal disease worldwide, characterized by low bone mineral density, resulting in weaker bones, and an increased risk of fragility fractures. The maintenance of bone mass relies on the precise balance between bone synthesis and resorption. The close relationship between the immune and skeletal systems, called "osteoimmunology", was coined to identify these overlapping "scientific worlds", and its function resides in the evaluation of the mutual effects of the skeletal and immune systems at the molecular and cellular levels, in both physiological and pathological states. Lipids play an essential role in skeletal metabolism and bone health. Indeed, bone marrow and its skeletal components demand a dramatic amount of daily energy to control hematopoietic turnover, acquire and maintain bone mass, and actively being involved in whole-body metabolism. Statins, the main therapeutic agents in lowering plasma cholesterol levels, are able to promote osteoblastogenesis and inhibit osteoclastogenesis. This review is meant to provide an updated overview of the pathophysiology of bone remodelling cycle, focusing on the interplay between bone, immune system and lipids. Novel therapeutic strategies for the management of osteoporosis are also discussed.

Cow milk allergy (CMA) is prevalently observed among infants and young children, exerting adverse effects on their growth and quality of life. Oral immune tolerance (OIT) is a more effective method for the prevention and treatment of CMA. The site of OIT is mainly in the gastrointestinal tract, so this article reviews the composition and structural characteristics of intestinal immune system, the molecular mechanisms of immune tolerance by regulatory T cells (Treg), dendritic cells, and gut microbiota. In addition, this paper summarizes the research progress of T cell epitope peptides of β-lactoglobulin and α-lactalbumin in whey protein hydrolysates. The mechanism of OIT induced by whey protein hydrolysate or whey protein combined with other anti-allergic components (phenolic compounds, probiotics, etc.) is overviewed to provide new ideas for the development of hypoallergenic infant formula.

Leishmania spp. infections pose a significant global health challenge, affecting approximately 1 billion people across more than 88 endemic countries. This unicellular, obligate intracellular parasite causes a spectrum of diseases, ranging from localized cutaneous lesions to systemic visceral infections. Despite advancements in modern medicine and increased understanding of the parasite's etiology and associated diseases, treatment options remain limited to pentavalent antimonials, liposomal amphotericin B, and miltefosine. A deeper understanding of the interactions between immune and non-immune cells involved in the clearance of Leishmania spp. infections could uncover novel therapeutic strategies for this debilitating disease. This review highlights recent progress in elucidating how various cell types contribute to the regulation and resolution of Leishmania spp. infections.

Despite recent advances in the treatment of Waldenström macroglobulenimia (WM), including the development of Bruton tyrosine kinase inhibitors (BTKis), the disease remains incurable highlighting the urgent need for new treatments. The overexpression of BCL2 in WM cells promotes cell survival by resisting apoptosis and contributes to resistance to chemotherapy and targeted therapies. Concurrently, Bcl2 proteins that are encoded by oncogenes supporting cell survival are frequently upregulated in WM, even in the presence of DNA-damaging agents, and hence have emerged as an alternative therapeutic target. Venetoclax serves as a novel orally administered small agent that targets Bcl-2 protein by acting as a BCL2 homology domain 3 (BH3) mimetic and has shown promising results in WM patients, including those previously treated with BTKis. Furthermore, venetoclax, in combination with standard WM regimens, has shown enhanced activity, but further studies are required to elucidate the mechanism of its synergistic action and identify the patients who can benefit from the combined therapy. New BCL2 inhibitors are in advanced stages of clinical development and may offer additional options. The present review will focus on the current knowledge we have on BCL2 inhibitors in WM, the input of these compounds "from bench to bedside," and their utility in managing relapsed/refractory WM patients.

Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.

Regulatory T (Treg) cells play a vital role in maintaining maternal immune tolerance to the semiallogeneic fetus during pregnancy. Treg cell population heterogeneity and tissue-specific functions in the human decidua remain largely unknown. Here, using single-cell transcriptomic and T cell receptor sequencing of human CD4+ T cells from first-trimester deciduae and matched peripheral blood of pregnant women, we identified a highly activated, immunosuppressive CCR8+ Treg cell subset specifically enriched in the decidua (dTreg cells). CCR8+ dTreg cells were decreased in patients with recurrent pregnancy loss (RPL) and an abortion-prone mouse model. Depletion of CCR8+ dTreg cells increased susceptibility to fetal loss, with altered decidual immune profiles. Adoptive transfer of CCR8+ Treg cells rescued fetal loss in abortion-prone mice. The CCR8 ligand CCL1 was mainly produced by decidual CD49a+ natural killer cells and was significantly decreased in patients with RPL. Our data demonstrate that CCR8+ dTreg cells are required to maintain maternal-fetal tolerance and highlight potential avenues for RPL therapies.

T-cell dysfunction is a hallmark of chronic lymphocytic leukemia (CLL), but the extent to which individual CD4+ or CD8+ T-cell subpopulations influence specific clinical events remains unclear. To address this knowledge gap, we utilised high-dimensional mass cytometry to profile circulating CD4+ and CD8+ T-cells in pre-treatment samples from a well-defined cohort of CLL patients undergoing initial therapy as part of a clinical trial.

Pre-treatment blood samples from 138 CLL patients receiving initial chemoimmunotherapy containing bendamustine or chlorambucil in the NCRI RIAltO trial (NCT01678430; EudraCT 2011-000919-22) were subjected to deep immunophenotyping by mass cytometry using a bespoke panel of 37 antibodies. T-cell clusters were identified through unsupervised clustering and related to treatment outcomes. Additionally, a randomly selected cohort of 30 CLL patients underwent T-cell stimulation with anti-CD3/CD28 microbeads, followed by cytokine analysis using a separate 36-antibody panel, which included seven cytokines.

Seventeen CD4+ and 22 CD8+ T-cell clusters were identified in a discovery cohort of 79 patients. Three of these clusters, measured as a proportion of their parental CD4+ or CD8+ populations, correlated with a reduced risk of grade ≥3 infection, grade ≥3 second primary malignancy (SPM) and death, respectively. Three corresponding T-cell subpopulations prospectively defined by non-redundant markers and Boolean gating (ICOS+HLA-DR+PD1+TIGIT+Tbet+CD4+ T-helper cells; CD27+CD28-PD1+Tbet+Eomes+CD8+ cells; and CD27+CD28-GrymB+Tbet+Eomes+CD8+ terminal effector cells) showed the same clinical correlations as the clusters on which they were based. With the exception of SPM for which there were insufficient events, these correlations were confirmed in a separate validation cohort of 59 patients. In-vitro stimulation of a subset of CLL patients in the discovery cohort showed an enrichment of primed and polyfunctional cells in all three Tbet+ T-cell subpopulations of interest.

Our study provides new insights into the potential for Tbet+ T-cell subpopulations to influence and predict specific clinical events in CLL. This, in turn, raises the possibility that these respective subpopulations could play an important role in controlling infection, solid tumours and CLL itself.

https://www.clinicaltrials.gov/, identifier NCT01678430; https://www.isrctn.com/ISRCTN09988575, identifier EudraCT 2011-000919-22.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous B cell neoplasm with variable clinical outcomes influenced by both tumor-derived and lymphoma microenvironment (LME) alterations. A recent transcriptomic study identifies four DLBCL subtypes based on LME characteristics: germinal center (GC)-like, mesenchymal (MS), inflammatory (IN), and depleted (DP). However, integrating this classification into clinical practice remains challenging. Here, we utilize deconvolution methods to assess microenvironment component abundance, establishing an LME classification of DLBCL using immunohistochemistry markers and digital pathology based on CD3, CD8, CD68, PD-L1, and collagen. This staining-based algorithm demonstrates over 80% concordance with transcriptome-based classification. Single-cell sequencing confirms that the immune microenvironments distinguished by this algorithm align with transcriptomic profiles. Significant disparities in overall and progression-free survival are observed among LME subtypes following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP with targeted agents (R-CHOP-X) immunochemotherapy. LME subtypes differed from distinct immune escape mechanisms, highlighting specific immunotherapeutic targets and supporting application of this classification in future precision medicine trials.

Hepatocellular carcinoma (HCC) constitutes a significant global health burden, and is characterized by limited early detection methods and poor survival rates. Golgi protein 73 (GP73), previously associated with liver-related diseases, has a controversial diagnostic value for HCC. The present study aimed to determine the diagnostic efficacy of serum GP73 (sGP73) levels in HCC and to explore their potential correlations with the development of HCC.

The levels of sGP73 and serum alpha-fetoprotein (sAFP) were measured in 134 HCC patients, 200 healthy controls (HCs), and 45 non-HCC patients with various liver diseases. Additionally, immunohistochemical staining was conducted on paraffin-embedded tissue samples obtained from 30 HCC patients to examine the expression of CD4+ T cells, CD8+ T cells, Foxp3+ Treg cells, Ki-67, and interferon-gamma (IFN-γ) in the tissue specimens.

sGP73 and sAFP were markedly higher in HCC patients than in HCs and non-HCC patients. However, sGP73 showed significantly higher sensitivity as a diagnostic marker for HCC than sAFP. The combination of sGP73 and sAFP further improved the accuracy (AUROC: 0.830). Besides, in the immunohistochemical staining analyses, sGP73-positive patients had lower expression of CD4+ and CD8+ T cells, higher expression of Foxp3+ Treg cells, higher expression of nuclear Ki67, and lower expression of IFN-γ than GP73-negative patients. In addition, sGP73-positive patients tended to have higher mortality rate, higher rate of metastasis, higher AFP levels, and more pronounced liver inflammation and damage than GP73-negative patients.

sGP73 could be utilized as a marker for the diagnosis of HCC, and may be implicated in the development of HCC through its interactions with the tumor microenvironment.

The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microorganisms with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1-4. Although RORγt+ antigen-presenting cells (APCs) have been shown to programme gut microbiota-specific pTreg cells5-7, their definition remains incomplete, and the APC responsible for food tolerance has remained unknown. Here we identify an APC subset that is required for differentiation of both food- and microbiota-specific pTreg cells and for establishment of oral tolerance. Development and function of these APCs require expression of the transcription factors PRDM16 and RORγt, as well as a unique Rorc(t) cis-regulatory element. Gene expression, chromatin accessibility, and surface marker analysis establish the pTreg-inducing APCs as myeloid in origin, distinct from type 3 innate lymphoid cells, and sharing epigenetic profiles with classical dendritic cells, and designate them PRDM16+RORγt+ tolerizing dendritic cells (tolDCs). Upon genetic perturbation of tolDCs, we observe a substantial increase in food antigen-specific T helper 2 cells in lieu of pTreg cells, leading to compromised tolerance in mouse models of asthma and food allergy. Single-cell analyses of freshly resected mesenteric lymph nodes from a human organ donor, as well as multiple specimens of human intestine and tonsil, reveal candidate tolDCs with co-expression of PRDM16 and RORC and an extensive transcriptome shared with tolDCs from mice, highlighting an evolutionarily conserved role across species. Our findings suggest that a better understanding of how tolDCs develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.