Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.

Immune checkpoint blockade (ICB) therapies have demonstrated significant clinical efficacy in immune-infiltrated tumors such as melanoma and non-small cell lung cancer. However, "cold tumors"-including ovarian cancer, pancreatic cancer, and gliomas-exhibit insufficient immune infiltration, leading to poor therapeutic responses to ICBs and limited improvement in patient prognosis. Recent studies have shown that tumor-associated tertiary lymphoid structures (TLSs) can induce strong local immune responses within the tumor microenvironment (TME), serving as important biological markers for predicting ICB therapy efficacy. Notably, preclinical and clinical studies on cold tumors have confirmed that TLSs can potently enhance ICB efficacy through TME remodeling-a breakthrough that has attracted considerable attention. Here, we systematically examine the immunological profile of cold tumors and decipher the mechanistic basis for their impaired immune cell infiltration. We further delineate the distinctive features of tumor-associated TLSs in generating antitumor immunity and establish criteria for their identification. Significantly, we emphasize the unique capability of TLSs to reprogram the immunosuppressive tumor microenvironment characteristic of cold tumors. Based on these insights, we evaluate clinical evidence supporting TLS-mediated enhancement of ICB efficacy and discuss emerging strategies for exogenous TLSs induction.

Immune homeostasis plays a crucial role in immunology andis dependent on both central and peripheral tolerance. Centraltolerance and peripheral tolerance occur in the thymus and thesecondary lymphoid tissues, respectively. Tolerance breakdown andimmune regulation defects can lead to autoimmune disorders. In thisreview article, we aimed to describe the role of exosomes inregulating central tolerance and provide a summary of their effectson the pathogenesis, diagnosis, and therapeutic potential inmyasthenia gravis (MG).

Articles for this review wereidentified using the PubMed database.

As the primarylymphoid organ, the thymus is responsible for building an immunecompetent, yet self-tolerant of T-cell population. Thymic statesinclude thymoma, thymic hyperplasia, and thymic atrophy, which canexert a significant influence on the central immune tolerance andrepresent specific characteristics of MG. Previous studies have foundthat exosomes derived from human thymic epithelial cells carryantigen-presenting molecules and a wide range of tissue restrictedantigens, which may indicate a vital role of thymic exosomes in MG.Besides, exosomal miRNAs and lncRNAs may also play a critical role inthe pathophysiology of MG.

This review provides thetherapeutic and diagnostic potential of exosomes in MG patients.

Transforming growth factor-β (TGF-β) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial-mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-β's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-β impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-β's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-β pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-β. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-β signaling in tumors and previous challenges, further research could yield innovative treatment strategies.

This study aimed to investigate the therapeutic potential of cell-free Dexamethasone (Dex) primed Wharton's jelly Mesenchymal stem cells derived conditioned media (DW) in addressing complications associated with systemic lupus erythematosus (SLE), focusing on its immunomodulatory effects.

Peripheral blood mononuclear cells from 74 SLE patients were stimulated and treated with Dex, DW and W. Culture supernatant were evaluated for autoantibody levels, IL-10 and TGF-β by ELISA, Treg subtypes, Breg subtypes, TH17 cells Double negative T cells and inflammatory neutrophils by flow cytometry, IL-10 and IL-17A by qPCR. In vivo studies were performed on 60 pristane induced female BALB/c mice. Dex and DW treatments were evaluated for autoantibody production, proteinuria, immunomodulation of immune cells, organ function, and histopathology. In vivo imaging of internal organs was done using VevoLAZR-X photoacoustic imaging system.

DW treatment significantly expanded different Treg and Bregs subtypes. DW suppressed pathogenic TH17, Double negative T cells and inflammatory neutrophils. Comparative analyses with hydroxychloroquine showed similar effects, with combined treatment enhancing efficacy. Inhibition studies implicated the TGF-β pathway in DW's mechanism. In vivo studies using the PIL mouse model showed that DW treatment reduced mortality, prevented proteinuria, and ameliorated symptoms such as limb inflammation, seizures, and alopecia. Detailed organ-specific evaluations through live imaging and histopathological analyses revealed DW's protective effects on kidneys, liver, lungs, heart, and spleen.

DW shows promise as a cell-free biological therapy for SLE and related autoimmune disorders, capable of modulating immune responses effectively without the adverse effects of glucocorticoids.

Periodontitis disease (PD) is a serious gum infection that progresses from gingivitis. PD is defined by gingival recession and bone loss and can lead to tooth loss. Bacterial infections are the main cause, as they induce inflammation and the development of periodontal pockets. Traditional therapies such as scaling and root planning aim to remove the subgingival biofilm via mechanical debridement but fail to address the fundamental inflammatory imbalance within the periodontium. The immune homeostasis linked to periodontal health necessitates a regulated immuno-inflammatory response, within which the presence of regulatory cells is critical to guarantee a managed response that reduces unintended tissue damage. Given that regulatory cells influence both innate and adaptive immunity, pathological conditions that might be alleviated through the establishment of immuno-tolerance, such as PD, could potentially gain from the application of regulatory cell immunotherapy. This review will reveal regulatory cell types, how they change phenotypes, and how they can be targets for new immunotherapies. As our understanding of regulatory cell biology advances, we can create novel therapeutics to improve their stability and function in PD.

Regulatory T (Treg) cells, which specifically express the master transcription factor FOXP3, have a pivotal role in maintaining immunological tolerance and homeostasis and have the potential to revolutionize cell therapies for autoimmune diseases1-3. Although stimulation of naive CD4+ T cells in the presence of TGFβ and IL-2 can induce FOXP3+ Treg cells in vitro (iTreg cells), the resulting cells are often unstable and have thus far hampered translational efforts4-6. A systematic approach towards understanding the regulatory networks that dictate Treg differentiation could lead to more effective iTreg cell-based therapies. Here we performed a genome-wide CRISPR loss-of-function screen to catalogue gene regulatory determinants of FOXP3 induction in primary human T cells and characterized their effects at single-cell resolution using Perturb-icCITE-seq. We identify the RBPJ-NCOR repressor complex as a novel, context-specific negative regulator of FOXP3 expression. RBPJ-targeted knockout enhanced iTreg differentiation and function, independent of canonical Notch signalling. Repeated cytokine and T cell receptor signalling stimulation in vitro revealed that RBPJ-deficient iTreg cells exhibit increased phenotypic stability compared with control cells through DNA demethylation of the FOXP3 enhancer CNS2, reinforcing FOXP3 expression. Conversely, overexpression of RBPJ potently suppressed FOXP3 induction through direct modulation of FOXP3 histone acetylation by HDAC3. Finally, RBPJ-ablated human iTreg cells more effectively suppressed xenogeneic graft-versus-host disease than control iTreg cells in a humanized mouse model. Together, our findings reveal novel regulators of FOXP3 and point towards new avenues to improve the efficacy of adoptive cell therapy for autoimmune disease.

Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.

Cardiovascular diseases remain the leading cause of mortality worldwide. Specifically, atherosclerosis is a primary cause of acute cardiac events. However, current therapies mainly focus on lipid-lowering versus addressing the underlying inflammatory response that leads to its development and progression. Nanoparticle-mediated drug delivery offers a promising approach for targeting and regulating these inflammatory responses. In atherosclerotic lesions, inflammatory cascades result in increased T helper (Th) 1 and Th17 activity and reduced T regulatory activation. The regulation of T cell responses is critical in preventing the inflammatory imbalance in atherosclerosis, making them a key therapeutic target for nanotherapy to achieve precise atherosclerosis treatment. By functionalizing nanoparticles with targeting modalities, therapeutic agents can be delivered specifically to immune cells in atherosclerotic lesions. In this Review, we outline the role of T cells in atherosclerosis, examine current nanotherapeutic strategies for targeting T cells and modulating their differentiation, and provide perspectives for the development of nanoparticles specifically tailored to target T cells for the treatment of atherosclerosis.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The primary therapies for HCC are liver transplantation, hepatic tumor excision, radiofrequency ablation, and molecular-targeted medicines. An unfavorable prognosis marks HCC and has limited pharmacological response in therapeutic studies. The tumor immune microenvironment (TME) imposes significant selection pressure on HCC, resulting in its evolution and recurrence after various treatments. As the principal cellular constituents of tumor-infiltrating lymphocytes (TILs), T cells have shown both anti-tumor and protumor actions in HCC. T cell-mediated immune responses are pivotal in cancer monitoring and elimination. TILs are recognized for their critical involvement in the progression, prognosis, and immunotherapeutic management of HCC. Foxp3 + , CD8 + , CD3 + , and CD4 + T cells are the extensively researched subtypes of TILs. This article examines the functions and processes of several subtypes of TILs in HCC. Emerging T cell-based therapies, including TILs and chimeric antigen receptor (CAR)-T cell therapy, have shown tumor regression in several clinical and preclinical studies. Herein, it also delves into the existing T cell-based immunotherapies in HCC, with emphasis on TILs and CAR-T cells.

iPSCs can serve as a renewable source of a consistent edited cell product, overcoming limitations of primary cells. While feeder-free generation of clinical grade iPSC-derived CD8 T cells has been achieved, differentiation of iPSC-derived CD4sp and regulatory T cells requires mouse stromal cells in an artificial thymic organoid. Here we report a serum- and feeder-free differentiation process suitable for large-scale production. Using an optimized concentration of PMA/Ionomycin, we generated iPSC-CD4sp T cells at high efficiency and converted them to Tregs using TGFβ and ATRA. Using genetic engineering, we demonstrated high, non-viral, targeted integration of an HLA-A2 CAR in iPSCs. iPSC-Tregs ± HLA-A2-targeted CAR phenotypically, transcriptionally and functionally resemble primary Tregs and suppress T-cell proliferation in vitro. Our work is the first to demonstrate an iPSC-based platform amenable to manufacturing CD4 T cells to complement iPSC-CD8 oncology products and functional iPSC-Tregs to deliver Treg cell therapies at scale.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder characterized by poorly reversible airway obstruction. COPD being an inflammatory disorder has been proposed to have an imbalance between proinflammatory and anti-inflammatory factors. Regulatory T cells (Tregs) being a negative regulator of immune response have been observed to play an important role in other inflammatory diseases as well as animal models of inflammation. Objective: This study is aimed at assessing the suppressive functions of circulatory Tregs and examining the inductive capacity of naive CD4+ T cells to generate induced Tregs. Methods: The study was conducted in 20 COPD patients (smokers n = 10; reformed smokers n = 10) and 20 age-matched healthy controls (smokers n = 10; nonsmokers n = 10). Peripheral blood mononuclear cells were isolated from blood using Ficoll density gradient separation. The suppressive functions were evaluated by assessing the proliferation of T responder cells (CD4+CD25-) in the presence of circulatory Tregs (CD4+CD25+) under polyclonal stimulation. In addition, cytokine-mediated suppression was assessed in the culture supernatants of the suppression assay. Inductive capacity was assessed by stimulating naive CD4+ T cells to generate iTregs in the presence of anti-CD3, IL-2, and TGF-β1. Results: The percent suppression of T responder cells by Tregs was significantly lower in COPD smokers (p = 0.03) and COPD reformed smokers (p = 0.04) as compared to control smokers. On the assessment of cytokine-mediated suppression, significantly reduced IL-2 in COPD S as compared to COPD RS (p < 0.05) and reduced IL-10 and TGFß1 in COPD S as compared to CNS (p < 0.05) and CS (p < 0.05) was observed in the culture supernatants of suppression assay. In addition, a significantly higher frequency of iTregs with phenotype CD4+CD25+CD45RA+CD127- was observed in COPD S as compared to COPD RS (p < 0.01). Discussion: Characteristics changes were observed in patients with COPD. The compromised Tregs function, despite the increase in systemic inflammation, suggests a potential role of these cells in the pathogenesis of the disease.

The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays a critical role in cancer progression. It comprises various cell types, including immune cells, tumor cells, and stromal cells. Among these, cancer-associated fibroblasts (CAFs) represent a heterogeneous population with diverse origins, phenotypes, and functions. Activated CAFs secrete multiple factors that promote tumor growth, migration, angiogenesis, and contribute to chemoresistance. Additionally, CAFs secrete extracellular matrix (ECM) components, such as collagen, which form a physical barrier that hinders the penetration of chemotherapeutic and immunotherapeutic agents. This ECM also influences immune cell infiltration, impeding their ability to effectively target tumor cells. As a result, modulating the activity of CAFs has emerged as a promising strategy to enhance the efficacy of tumor immunotherapy. Nano-delivery systems, constructed from various nanomaterials with high targeting specificity and biocompatibility, offer a compelling approach to deliver therapeutic agents or immunomodulatory factors directly to CAFs. This modulation can alter CAF function, reduce their tumor-promoting effects, and thereby improve the outcomes of immunotherapy. This review provides an in-depth exploration of the origins, functions, and interactions of CAFs within the TME, particularly in the context of immune suppression. Furthermore, it discusses the potential applications of functional nanocarrifers in modulating CAFs and enhancing the effectiveness of tumor immunotherapy, highlighting the significant progress and potential of nanotechnology in this area.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain malignancies in adults. Standard approaches, including surgical resection followed by adjuvant radio- and chemotherapy with temozolomide (TMZ), provide only transient control, as GBM frequently recurs due to its infiltrative nature and the presence of therapy-resistant subpopulations such as glioma stem cells (GSCs). GSCs, with their quiescent state and robust resistance mechanisms, evade conventional therapies, contributing significantly to relapse. Consequently, current treatment methods for GBM face significant limitations in effectively targeting GSCs. In this review, we emphasize the relationship between GBM recurrence and GSCs, discuss the current limitations, and provide future perspectives to overwhelm the challenges associated with targeting GSCs. Eliminating GSCs may suppress recurrence, achieve durable responses, and improve therapeutic outcomes for patients with GBM.

TGM6 is a natural antagonist of mammalian TGF-β signaling produced by the murine helminth parasite Heligmosomoides polygyrus. It differs from the previously described agonist, TGM1 (TGF-β Mimic-1), in that it lacks domains 1/2 that bind TGFBR1. It nonetheless retains TGFBR2 binding through domain 3 and potently inhibits TGF-β signaling in fibroblasts and epithelial cells, but does not inhibit TGF-β signaling in T cells, consistent with divergent domains 4/5 and an altered co-receptor binding preference. The crystal structure of TGM6 bound to TGFBR2 reveals an interface remarkably similar to that of TGF-β with TGFBR2. Thus, TGM6 has adapted its structure to mimic TGF-β, while engaging a distinct co-receptor to direct antagonism to fibroblasts and epithelial cells. The co-expression of TGM6, along with immunosuppressive TGMs that activate the TGF-β pathway, may minimize fibrotic damage to the host as the parasite progresses through its life cycle from the intestinal lumen to submucosa and back again. The co-receptor-dependent targeting of TGFBR2 by the parasite provides a template for the development of therapies for targeting the cancer- and fibrosis-promoting activities of the TGF-βs in humans.

In colorectal cancer (CRC), increased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells correlate with tumor development, immunotherapy failure, and poor prognosis. To assess how CRC tumors directly modulate Treg cell differentiation, we developed an in vitro co-culture system using CD4+ T cells from Foxp3eGFP mice and CRC tumor-derived organoids. Co-culture resulted in a significant increase in Treg cell numbers. RNA-sequencing identified a distinct transcriptional profile of CRC organoid-induced Treg cells, with upregulation of genes associated with CRC Treg cells in vivo. High expression of genes upregulated in CRC organoid-induced Treg cells correlates with shorter progression-free intervals and overall survival in CRC patients. Human CRC organoids similarly induced Treg cells with enhanced suppressive capacity and upregulated genes linked to CRC Treg cells in vivo. This model provides insights into how CRC tumors modulate CD4+ T cell differentiation and can identify approaches to disrupt Treg cells and stimulate anti-tumor immunity.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by recurrent inflammatory relapses and neurodegeneration. Myeloid cells play a critical role in shaping the inflammatory environment and influencing disease progression. Here, we demonstrate that activation of the Wnt signaling pathway reprograms myeloid cells into an immunoregulatory phenotype, leading to reduced neuroinflammation and disease severity. Using both experimental autoimmune encephalomyelitis (EAE) and human-derived myeloid cells, we show that Wnt agonist treatment promotes the expression of inhibitory molecules such as PD-L1 and PD-L2, suppressing pro-inflammatory responses. In the chronic and relapsing-remitting EAE models, Wnt activation significantly reduced disease severity, immune cell infiltration into the CNS, and pathogenic T cell responses. Notably, in relapsing-remitting EAE, Wnt treatment prevented new relapses in a PD-L1-dependent manner, highlighting the crucial role of myeloid cell-mediated immune regulation. These findings reveal a previously unrecognized role for Wnt signaling in myeloid cell immunoregulation and suggest that targeting this pathway could provide a novel therapeutic strategy for MS and other autoimmune diseases.

In pancreatic ductal adenocarcinoma (PDAC), stromal cells and matrix proteins form a dense physical barrier that, while preventing the outward spread of tumor cells, also limits the penetration of drugs and CD8+ T cells inward. Additionally, the overactivated TGF-β/SMAD signaling pathway further promotes matrix proliferation and immune suppression. Therefore, crossing the stromal barrier while preserving the integrity of the stroma, releasing drugs intratumorally, remodeling the stroma, and activating the immune system is a promising drug delivery strategy. In this work, a type of enamine N-oxides modified nanoparticle was prepared, with stearic acid-modified gemcitabine prodrug (GemC18) and pSMAD2/3 inhibitor galunisertib encapsulated. The peripheral enamine N-oxides can trigger transcytosis and then respond to hypoxia and acidic microenvironments, turning the surface charge of the nanoparticles to a positive charge and enhancing penetration. The released galunisertib inhibits the TGF-β/SMAD signaling pathway, reshapes the matrix, activates antitumor immunity, and combines with gemcitabine (Gem) to kill tumor cells.

In recent years, the relationship between the immunosuppressive niche of the bone marrow and therapy resistance in acute myeloid leukemia (AML) has become a research focus. The abnormal number and function of immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), along with the dysfunction and exhaustion of immunological effector cells, including cytotoxic T lymphocytes (CTLs), dendritic cells (DCs) and natural killer cells (NKs), can induce immune escape of leukemia cells and are closely linked to therapy resistance in leukemia. This article reviews the research progress on the relationship between immune cells in the marrow microenvironment and chemoresistance in AML, aiming to provide new ideas for the immunotherapy of AML.

T cells play a critical and irreplaceable role in maintaining overall health. However, their functions undergo alterations as individuals age. It is of utmost importance to comprehend the specific characteristics of T-cell aging, as this knowledge is crucial for gaining deeper insights into the pathogenesis of aging-related diseases and developing effective therapeutic strategies. In this review, we have thoroughly examined the existing studies on the characteristics of immune organ aging. Furthermore, we elucidated the changes and potential mechanisms that occur in T cells during the aging process. Additionally, we have discussed the latest research advancements pertaining to T-cell aging-related diseases. These findings provide a fresh perspective for the study of T cells in the context of aging.

Transforming growth factor beta (TGF-β) is a pluripotent cytokine expressed by all cells of the human body which plays important roles in maintaining homeostasis and allowing for proper individual development. Disturbances in TGF-β signaling contribute to the development of many diseases and disorders, including cancer and organ fibrosis. One of the diseases with the best-characterized correlation between TGF-β action and etiopathogenesis is asthma. Asthma is the most common chronic inflammatory disease of the lower and upper respiratory tract, characterized by bronchial hyperresponsiveness to a number of environmental factors, leading to bronchospasm and reversible limitation of expiratory flow. TGF-β, in particular TGF-β1, is a key factor in the etiopathogenesis of asthma. TGF-β1 concentration in bronchoalveolar lavage fluid samples is elevated in atopic asthma, and TGF-β expression is increased in asthmatic bronchial samples. The expression of all TGF-β isoforms is affected by a number of single nucleotide polymorphisms found in the genes encoding these cytokines. Some of the SNPs that alter the level of TGF-β expression may be associated with the occurrence and severity of symptoms of asthma and other diseases. The TGF-β gene polymorphisms, which are the subject of this paper, are potential diagnostic factors. If properly used, these polymorphisms can facilitate the early and precise diagnosis of asthma, allowing for the introduction of appropriate therapy and reduction of asthma exacerbation frequency.

There are limited studies on the improvement of leaky gut with minor inflammation associated with various diseases. To explore the therapeutic potential of Lactiplantibacillus plantarum 22 A-3, a member of the Lactobacillus species, in addressing a leaky gut. Lactiplantibacillus plantarum 22 A-3 was administered to a leaky gut mice model with low dextran sulfate sodium concentrations. The Lactiplantibacillus plantarum 22 A-3-treated group exhibited amelioration of increased intestinal permeability, as indicated by lower blood fluorescein isothiocyanate-dextran levels compared with that of the control group. Furthermore, the messenger RNA expression of interleukin-10, an anti-inflammatory cytokine, was upregulated in the small intestine of Lactiplantibacillus plantarum 22 A-3-treated mice. Moreover, forkhead box P3 was upregulated in the small intestine and colon following Lactiplantibacillus plantarum 22 A-3 administration. Flow cytometry showed that forkhead box P3-positive regulatory T cells tended to increase in the small intestine and colon; however, this was not significant. Messenger RNA levels for the pro-inflammatory cytokines, interleukin-1 beta, and tumor necrosis factor-alpha showed no significant changes in the small intestine; however, their expressions significantly decreased in the colon. Blood fluorescein isothiocyanate-dextran levels showed that intestinal permeability also decreased in Lactiplantibacillus plantarum 22 A-3-dead bacteria. The bacterial component of Lactiplantibacillus plantarum 22 A-3 ameliorates increased intestinal permeability through its anti-inflammatory effect in the intestinal tract and may be a novel treatment for leaky gut.

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) play a crucial role in the tumor microenvironment (TME), influencing the progression, prognosis, and response to treatment in oral squamous cell carcinoma (OSCC) and its precursors, oral potentially malignant disorders (OPMDs). This scoping review assesses the current literature on TILs in the TME of OSCC and OPMDs, aiming to identify trends and gaps in the research. Methods: A comprehensive search was performed in PubMed, using the following query terms: "Tumor Microenvironment AND (mouth neoplasms OR oral lichen OR leukoplakia OR oral lichenoid OR dysplasia OR GVHD OR lupus)". Based on the inclusion criteria, we selected in vivo human original research and clinical observational studies that focused on TILs within the TME of OSCC and OPMDs. Results: Out of 1152 results in PubMed, 58 studies were selected and analyzed. These studies investigated various TILs, including T cells, B cells, and natural killer (NK) cells. Of these, 47 studies focused on the OSCC TME, 4 examined the OPMDs ME, and 7 compared OSCC TME and OPMDs ME. Discussion: While TILs in OSCC have been extensively studied, research on infiltrating lymphocytes in OPMDs is still limited. In OSCC, CD8+ T cells, T helper 1 cells, and NK cells are associated with strong antitumor activity, whereas CD4+ T cells, including T helper 2 and regulatory T cells, are linked to protumoral effects. B cells remain less explored due to their low frequency in the TME. In OPMDs, trends suggest an increase in activated CD8+ T cells in OLP and lower NK cell numbers compared to OSCC, which may contribute to malignant transformation. Understanding the spatial distribution and activation status of TILs within the TME is essential for deciphering their role. The variability in TIL composition highlights the complexity of the TME. Conclusions: Current knowledge remains preliminary, though it highlights the crucial role of TILs in carcinogenesis and OSCC. A more in-depth understanding could improve diagnostic and therapeutic strategies, including the assessment of the risk of malignant transformation in OPMDs.

Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.

Previously, we reported that both S-nitrosoglutathione (GSNO), a carrier of cellular nitric oxide, and N6022, an injectable form of GSNO reductase (GSNOR) inhibitor that increases endogenous GSNO levels, alleviate experimental autoimmune encephalomyelitis (EAE) in mice by suppressing Th1 and Th17 immune responses. Building on these findings, we explored the role of GSNOR in EAE pathogenesis and evaluated the efficacy of an orally active GSNOR inhibitor (N91115) in treating the EAE disease. EAE mice exhibited heightened expression/activity of GSNOR in the spinal cord, and the knockout of the GSNOR gene resulted in much milder clinical manifestations of EAE, with lower degrees of demyelination and axonal loss, reduced microglial and astrocyte activations, as well as suppressed Th1 and Th17 cell responses, alongside bolstered Treg immune responses. Next, we evaluated the efficacy of N91115 against EAE immunopathology. Consistent with our findings in GSNOR deficient EAE mice, daily N91115 administration reduced clinical EAE severity, with less spinal cord demyelination and axonal loss compared to untreated EAE mice. Furthermore, N91115 treated EAE mice showed diminished Th1 and Th17 immune responses and enhanced Treg responses. This observation underscores the potential of increased GSNOR expression and activity as a risk factor exacerbating EAE immunopathology, while simultaneously highlighting its potential as a target for modifying the disease. Furthermore, the balanced immune regulation provided by orally active N91115 (IL-6/IL-17a vs. IL-10) presents a promising alternative to immunosuppressive drugs, reducing the risk of opportunistic infections.

The immunologic factors are the chief reason for recurrent pregnancy loss (RPL) and induction of maternal-fetal tolerance is the main treatment for this cause of RPL, but the effect of this method is uncertainly and needs multiple doses and/or interventions. The aim of this study was to investigate whether a single administration of transforming growth factor-β1 (TGF-β1) can improve the pregnancy outcomes of RPL mice and whether the improvement is cause by TGF-β1 driving the expression of immune tolerance molecule indoleamine 2,3-dioxygenase (IDO).

In this experimental study, 40 RPL model mice were equally divided into a control group, that received 0.01 M phosphate-buffered saline (PBS), and a treatment group, that received PBS containing 2, 20, and 200 ng/ml TGF-β1 via tail vein injection. The mice were sacrificed at 13.5 days of pregnancy and the embryo resorption rate was determined. The expression of IDO, TGF-β1, and TGF-β3 were detected in the placenta using western blotting and immunohistochemistry techniques.

The expression of IDO was positively correlated with TGF-β1 in the placental tissue of RPL mice (r=0.591, P<0.001). In all treatment groups, the embryo resorption rates were significantly lower than the control group and the expression of IDO in the placental tissue of all treatment groups was significantly higher than the control group. The expression of TGF-β1 increased gradually from, 2, 20 to 200 ng/ml in treatment groups, and the concentration of exogenous TGF-β1 positively correlated with the expression of TGF-β1, in placental tissues in treatment groups (r=0.372, P=0.018).

Exogenous TGF-β1 improves pregnancy outcomes in RPL mice, and the possible therapeutic mechanism is that exogenous TGF-β1 induces the persistent expression of endogenous TGF-β1 and IDO due to mutually induced expression of the other. This experiment may provide a new direction and idea for the future treatment of RPL patients.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by enhanced platelet destruction and impaired platelet production, due to a loss of immune tolerance that leads to targeting of platelets and megakaryocytes by glycoprotein-autoantibodies and/or cytotoxic T cells. There is a high degree of heterogeneity in ITP patients signified by unpredictable disease trajectories and treatment responses. Initial studies in humans have identified intestinal microbiota perturbance in ITP. Recently, gut microbial perturbance has been linked to other autoimmune diseases. Based on these findings, we hypothesize that intestinal microbiota may influence ITP pathophysiology through several mechanisms, including induction of platelet-autoantibody production, increasing complement-dependent platelet cytotoxicity, disturbing T cell homeostasis, impairing megakaryocyte function, and increasing platelet-desialylation and -clearance. The pathophysiological heterogeneity of ITP may, at least in part, be attributed to a perturbed intestinal microbiota. Therefore, a better understanding of intestinal microbiota in ITP may result in a more personalized therapeutic approach.

Regulatory T cells (Tregs) have emerged as crucial players in maintaining maternal-fetal tolerance and promoting successful pregnancy outcomes. This review examines the importance of these cells in pregnancy, drawing on human and animal-based studies, with a focus on their role in bovine fertility. Tregs employ various mechanisms to mediate maternal-fetal tolerance, including regulation of effector T-cell responses, interactions with innate immune cells in the uterine microenvironment, and modulation of trophoblast function. In humans, Treg dynamics during normal pregnancy and alterations in pregnancy complications provide compelling evidence for their involvement in maintaining fetal-maternal harmony. Animal models, particularly mouse studies, have further elucidated the importance of Tregs in preventing fetal rejection and promoting successful pregnancy outcomes. The review also explores the characterization of bovine Tregs, highlighting their similarities and unique features compared to human and rodent counterparts. Recent studies have indicated the presence and potential significance of Tregs in the bovine uterine environment during early pregnancy. Translational applications of Treg research in livestock fertility are discussed, with a focus on immunomodulatory strategies for enhancing Treg function, such as antigen-specific tolerance induction, pharmacological targeting of Treg pathways, and cell-based therapies using autologous or allogeneic Tregs. The review concludes by emphasizing the potential impact of Treg-based strategies on the livestock industry and the broader implications for human reproductive health. Future research directions are outlined, underscoring the need for further investigations into the role of Tregs in bovine reproductive tissues and their relationship with fertility outcomes.

Type 1 diabetes (T1D) results in autoreactive T cells chronically destroying pancreatic islets. This often results in irreplaceable loss of insulin-producing beta cells. To reverse course, a combinatorial strategy of employing glucose-responsive insulin restoration coupled with inhibiting autoreactive immune responses is required.

Non-obese diabetic mice received a single intraperitoneal implantation of a novel biomaterial co-seeded with insulin-producing islets and T regulatory cells (Tregs). Controls included biomaterial seeded solely with islets, or biomaterial only groups. Mice were interrogated for changes in inflammation and diabetes progression via blood glucose monitoring, multiplex serum cytokine profiling, flow cytometry and immunohistochemistry assessments.

Islet and Tregs co-seeded biomaterial recipients had increased longevity, insulin secretion, and normoglycemia through 180 days post-implantation compared to controls. Serum profile revealed reduced TNFα, IFNγ, IL-1β and increased IL-10, insulin, C-Peptide, PP and PPY in recipients receiving co-seeded biomaterial. Evaluation of the resected co-seeded biomaterial revealed reduced infiltrating autoreactive CD8 + and CD4 + T cells concomitant with sustained presence of Foxp3 + Tregs; further analysis revealed that the few infiltrated resident effector CD4+ or CD8+ T cells were anergic, as measured by low levels of IFNγ and Granzyme-B upon stimulation when compared to controls. Interestingly, studies also revealed increased Tregs in the pancreas. However, there was no restoration of the pancreas beta cell compartment, suggesting normoglycemia and production of insulin levels were largely supported by the implanted co-seeded biomaterial.

These studies show the efficacy of a combinatorial approach seeding Tregs with pancreatic islets in a novel self-assembling organoid for reversing T1D.

Pancreatic cancer, referred to as the "monarch of malignancies," is a neoplastic growth mostly arising from the epithelial cells of the pancreatic duct and acinar cells. This particular neoplasm has a highly unfavorable prognosis due to its marked malignancy, inconspicuous initial manifestation, challenging early detection, rapid advancement, and limited survival duration. Cellular immunotherapy is the ex vivo culture and expansion of immune effector cells, granting them the capacity to selectively target malignant cells using specialized techniques. Subsequently, these modified cells are reintroduced into the patient's organism with the purpose of eradicating tumor cells and providing therapeutic intervention for cancer.

Presently, the primary cellular therapeutic modalities employed in the treatment of pancreatic cancer encompass CAR T-cell therapy, TCR T-cell therapy, NK-cell therapy, and CAR NK-cell therapy.

This review provides a concise overview of the mechanisms and primary targets associated with various cell therapies. Additionally, we will explore the prospective outlook of cell therapy in the context of treating pancreatic cancer.

Classic regulatory T (Treg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of Treg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the Treg paradox', we provide an overview of Treg cell biology with a focus on Treg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of Treg cells while also promoting the differentiation of TH17-like Treg cell, exTreg cell (effector T cells that were formerly Treg cells), and osteoclastogenic Treg cell subsets that mediate tissue injury. We present a new framework to understand Treg cells in joint inflammation and define potential strategies for Treg cell-directed interventions in human inflammatory arthritis.

Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.

Gastric cancer (GC) represents a prevalent malignancy globally, often diagnosed at advanced stages owing to subtle early symptoms, resulting in a poor prognosis. Exosomes are extracellular nano-sized vesicles and are secreted by various cells. Mounting evidence indicates that exosomes contain a wide range of molecules, such as DNA, RNA, lipids, and proteins, and play crucial roles in multiple cancers including GC. Recently, with the rapid development of mass spectrometry-based detection technology, researchers have paid increasing attention to exosomal cargo proteins. In this review, we discussed the origin of exosomes and the diagnostic and prognostic roles of exosomal proteins in GC. Moreover, we summarized the biological functions of exosomal proteins in GC processes, such as proliferation, metastasis, drug resistance, stemness, immune response, angiogenesis, and traditional Chinese medicine therapy. In summary, this review synthesizes current advancements in exosomal proteins associated with GC, offering insights that could pave the way for novel diagnostic and therapeutic strategies for GC in the foreseeable future.

Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR'336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR'336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells' proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR'336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR'336 promoted the differentiation of IL-33-responsive (ST2+), IL-10-producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR'336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.

Memory-phenotype (MP) CD4+ T lymphocytes develop from naïve cells via self-recognition at homeostasis. While previous studies defined MP cells as a heterogeneous population that comprises T helper 1 (TH1)/17-like subsets, functional significance of the T-bet- Rorγt- subpopulation remains unknown. Here we show that MP lymphocytes as a whole population can differentiate into TH1/17/regulatory T (Treg) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, TH1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only TH1/17-differentiated subsets but a polyclonal, transcriptomically immature "undifferentiated" subpopulation at homeostasis. Furthermore, our data argue that while the T-bet+ Rorγt- MP subset is terminally TH1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into TH1/17/Treg cells, with the latter response tonically constrained by preexisting Treg cells. Together, our results identify undifferentiated MP CD4+ T lymphocytes as a unique precursor that has a diverse differentiation potential to generate TH1/17/Treg cells to contribute to pathogenesis of inflammation.

Human papillomavirus (HPV) is involved in virtually all cases of cervical cancer. However, HPV alone is not sufficient to cause malignant development. The effects of chronic inflammation and the interaction of immune components with the microenvironment infected with the high-risk HPV type (HR) may contribute to cancer development. Transforming growth factor β (TGFB) appears to play an important role in cervical carcinogenesis. Protein and mRNA levels of this cytokine gradually increase as normal tissue develops into malignant tissue and are closely related to the severity of HPV infection. At the onset of infection, TGFB can inhibit the proliferation of infected cells and viral amplification by inhibiting cell growth and downregulating the transcriptional activity of the long control region (LCR) of HPV, thereby reducing the expression of early genes. When infected cells progress to a malignant phenotype, the response to the cell growth inhibitory effect of TGFB1 is lost and the suppression of E6 and E7 expression decreases. Subsequently, TGFB1 expression is upregulated by high levels of E6 and E7 oncoproteins, leading to an increase in TGFB1 in the tumor microenvironment, where this molecule promotes epithelial-to-mesenchymal transition (EMT), cell motility, angiogenesis, and immunosuppression. This interaction between HPV oncoproteins and TGFB1 is an important mechanism promoting the development and progression of cervical cancer.

Immune-mediated inflammatory disease (IMID) is a complex disorder characterized by excessive immune responses involving T cells and their subsets, leading to direct tissue damage. T cells can be broadly categorized into CD4+ T cells and CD8+ T cells. CD4+ T cells are composed of several subsets, including T helper (Th)1, Th2, Th9, Th17, Th22, follicular helper T cells (Tfhs), and regulatory T cells (Tregs), while effector CD8+ T cells consist mainly of cytotoxic T cells (CTLs). Current therapies for IMID are ineffective, prompting exploration into mesenchymal stem cells (MSCs) as a promising clinical treatment due to their immunomodulatory effects and self-renewal potential. Recent studies have shown that MSCs can suppress T cells through direct cell-to-cell contact or secretion of soluble cytokines. Nevertheless, the precise effects of MSCs on T cell subsets remain inadequately defined. In this review, we summarize the most recent studies that have examined how MSCs modulate one or more effector T-cell subsets and the mechanisms behind these modifications in vitro and several mouse models of clinical inflammation. This also provides theoretical support and novel insights into the efficacy of clinical treatments involving MSCs. However, the efficacy of MSC therapies in clinical models of inflammation varies, showing effective remission in most cases, but also with exacerbation of T-cell-mediated inflammatory damage in some instances.

Spinal cord injury (SCI) is a serious and disabling injury that is often accompanied by neuropathic pain (NeP), which severely affects patients' motor and sensory functions and reduces their quality of life. Currently, there is no specific treatment for treating SCI and relieving the accompanying pain, and we can only rely on medication and physical rehabilitation, both of which are ineffective. Researchers have recently identified a novel class of glial cells, olfactory ensheathing cells (OECs), which originate from the olfactory system. Transplantation of OECs into damaged spinal cords has demonstrated their capacity to repair damaged nerves, improve the microenvironment at the point of injury, and They can also restore neural connectivity and alleviate the patient's NeP to a certain extent. Although the effectiveness of OECs transplantation has been confirmed in experiments, the specific mechanisms by which it repairs the spinal cord and relieves pain have not been articulated. Through a review of the literature, it has been established that the ability of OECs to repair and relieve pain is inextricably linked to its anti-inflammatory and immunomodulatory effects. In this regard, it is imperative to gain a deeper understanding of how OECs exert their anti-inflammatory and immunomodulatory effects. The objective of this paper is to provide a comprehensive overview of the mechanisms by which OECs exert anti-inflammatory and immunomodulatory effects. We aim to manipulate the immune microenvironment at the transplantation site through the intervention of cytokines and immune cells, with the goal of enhancing OECs' function or creating a conducive microenvironment for OECs' survival. This approach is expected to improve the therapeutic efficacy of OECs in clinical settings. However, numerous fundamental and clinical challenges remain to be addressed if OEC transplantation therapy is to become a standardized treatment in clinical practice.