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Background: HBV-specific T lymphocytes are pivotal in eliminating the hepatitis B virus (HBV) and regulating intrahepatic inflammatory reactions. Effective T cell responses curtail HBV infection; however, compromised immunity can result in persistent infection. Beyond the acute phase, the continued presence of antigens and inflammation leads to the increased expression of various inhibitory receptors, such as PD-1, CTLA-4, Tim-3, LAG3, 2B4, CD160, BTLA, and TIGIT. This escalates the dysfunction of and diminishes the immune and proliferative abilities of T cells. Methods: In this study, we reviewed English-language literature from PubMed, Web of Science, and Scopus up to 9 July 2023. This paper aims to elucidate the inhibitory effects of these receptors on HBV-specific T lymphocytes and how immune function can be rejuvenated by obstructing the inhibitory receptor signaling pathway in chronic HBV patients. We also summarize the latest insights into related anti-HBV immunotherapy. Result: From 66 reviewed reports, we deduced that immunotherapy targeting inhibitory receptors on T cells is a reliable method to rejuvenate T cell immune responses in chronic HBV patients. However, comprehensive combination therapy strategies are essential for a functional cure. Conclusions: Targeting T cell suppressor receptors and combining immunotherapy with antiviral treatments may offer a promising approach towards achieving a functional cure, urging future research to prioritize effective combination therapeutic strategies for chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background: In the global effort to discover biomarkers for cancer prognosis, prediction tools have become essential resources. TCR (T cell receptor) repertoires contain important features that differentiate healthy controls from cancer patients or differentiate outcomes for patients being treated with different drugs. Considering, tools that can easily and quickly generate and identify important features out of TCR repertoire data and build accurate classifiers to predict future outcomes are essential. Results: This paper introduces GENTLE (GENerator of T cell receptor repertoire features for machine LEarning): an open-source, user-friendly web-application tool that allows TCR repertoire researchers to discover important features; to create classifier models and evaluate them with metrics; and to quickly generate visualizations for data interpretations. We performed a case study with repertoires of TRegs (regulatory T cells) and TConvs (conventional T cells) from healthy controls versus patients with breast cancer. We showed that diversity features were able to distinguish between the groups. Moreover, the classifiers built with these features could correctly classify samples ('Healthy' or 'Breast Cancer')from the TRegs repertoire when trained with the TConvs repertoire, and from the TConvs repertoire when trained with the TRegs repertoire. Conclusion: The paper walks through installing and using GENTLE and presents a case study and results to demonstrate the application's utility. GENTLE is geared towards any researcher working with TCR repertoire data and aims to discover predictive features from these data and build accurate classifiers. GENTLE is available on https://github.com/dhiego22/gentle and https://share.streamlit.io/dhiego22/gentle/main/gentle.py. [ABSTRACT FROM AUTHOR]

Allergen-immunotherapy (AIT) is an efficacious and disease-modifying treatment option for IgE-mediated diseases. Among these allergic rhinitis, insect venom allergy, food allergy, and allergic asthma are the most common candidates for AIT. AIT gives rise to clinical immunotolerance which may last for years after the treatment cessation. Mechanisms of AIT include suppression of allergic inflammation in target tissues and stimulation of the production of blocking antibodies, especially IgG4 and IgA. These mechanisms are followed by a reduction of underlying allergen-specific Th2 cell-driven responses to the allergens. Tolerance induction takes place through the desensitization of effector cells and stimulation of regulatory T cells that show their effects by mechanisms involving cell-cell cross-talk, but also other mechanisms, e.g., by the production of immunomodulatory cytokines such as, e.g., IL-10 and TGF-beta. From a personalized medical perspective, there is a need for clinical biomarkers of value in selecting responders and optimizing patient care during AIT. Also, a deeper understanding of underlying mechanistic processes will improve AIT's future outcomes. In this paper, the current knowledge of mechanisms in AIT is reviewed with a special focus on biomarkers of this therapy. [ABSTRACT FROM AUTHOR]

Tumor cells express a high quantity of exosomes packaged with unique cargos under hypoxia, an important characteristic feature in solid tumors. These hypoxic tumor-derived exosomes are, crucially, involved in the interaction of cancer cells with their microenvironment, facilitating not only immune evasion, but increased cell growth and survival, enhanced angiogenesis, epithelial–mesenchymal transition (EMT), therapeutic resistance, autophagy, pre-metastasis, and metastasis. This paper explores the tumor microenvironment (TME) remodeling effects of hypoxic tumor-derived exosome towards facilitating the tumor progression process, particularly, the modulatory role of these factors on tumor cell immune evasion through suppression of immune cells, expression of surface recognition molecules, and secretion of antitumor soluble factor. Tumor-expressed exosomes educate immune effector cells, including macrophages, monocytes, T cells, natural killer (NK) cells, dendritic cells (DCs), γδ T lymphocytes, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mast cells, and B cells, within the hypoxic TME through the release of factors that regulate their recruitment, phenotype, and function. Thus, both hypoxia and tumor-derived exosomes modulate immune cells, growth factors, cytokines, receptor molecules, and other soluble factors, which, together, collaborate to form the immune-suppressive milieu of the tumor environment. Exploring the contribution of exosomal cargos, such as RNAs and proteins, as indispensable players in the cross-talk within the hypoxic tumor microenvironmental provides a potential target for antitumor immunity or subverting immune evasion and enhancing tumor therapies. [ABSTRACT FROM AUTHOR]

• FOXP3 controls Treg differentiation and activity. • FOXP3 induces metabolic versatility in intra-tumoral Tregs. • Treg subsets show different reliance on FOXP3. Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens–associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper. [ABSTRACT FROM AUTHOR]

Summary: The immune system plays a critical role in protecting the host against infection but is subject to numerous levels of control that are necessary to prevent pathological, tissue-damaging responses. Inappropriate inflammatory immune responses to self-antigens, innocuous commensal microorganisms, or environmental antigens can lead to chronic, debilitating, and degenerative diseases. Regulatory T cells have an essential, non-redundant, and dominant function in preventing pathological immune responses, as shown by the development of systemic fatal autoimmunity in humans and animals with a genetic deficiency in regulatory T cells. In addition to controlling immune responses, there is a growing understanding that regulatory T cells also contribute directly to tissue homeostasis by promoting tissue regeneration and repair. For these reasons, the prospect of enhancing regulatory T-cell numbers and/or function in patients represents an appealing therapeutic opportunity with potential applications in many diseases, including some where the pathological role of the immune system has only recently been recognized. Approaches to enhance regulatory T cells are now starting to be explored in clinical studies in humans. This review series brings together papers highlighting the Treg-enhancing approaches that are most advanced clinically and examples of therapeutic opportunities based on our growing understanding of regulatory T-cell functions. [ABSTRACT FROM AUTHOR]

Background: Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM. Results: Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2. Conclusion: The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice. [ABSTRACT FROM AUTHOR]

The Th17/ Treg axis is a crucial regulator of anti-inflammatory and proinflammatory pathways that play fundamental roles in cancer and autoimmune diseases. The alteration of the Th17/Tregs axis is highly significant for developing novel therapeutic approaches. Th17 and Treg cells share a large portion of their transcriptome, albeit with distinct functions. The mechanisms governing the bifurcation of Th17 /Treg axis differentiation from naïve T cells are not yet understood. This study aims to identify the differentially expressed genes (DEGs) and gene-enriched pathways that contribute to the distinction between these closely aligned phenotypes. We analyzed RNA sequencing data of CD4+ T cells differentiated in vitro into Th0, Th17, and Tregs phenotypes and built gene enrichment networks. We studied the network rewiring of Th17 and Tregs from Th0 cells. In addition to common pathways and genes that are equally expressed between these two distinct phenotypes, we identified key genes and pathways that contribute to their distinctiveness. For example, the Keap1 gene and several of its interactors such as MCC1 were upregulated in Tregs indicating that Tregs possess mechanisms that prevent the over-activation of antioxidants pathways. Tregs also possess several genes that are involved in the hydrolysis of ATP to ADP as RAB37, ATP1A2, ATP1B, and PDE2A to ensure Treg anti-inflammatory capabilities. Additionally, one of the pathways that ensure Tregs differentiation and function seems to point toward an insulin role mediated by APOL9B and GOLM. Taken together our findings shed light on various essential regulators of the Th17/Treg axis and pave the way for treatment strategies that selectively target one phenotype while sparing the other. [ABSTRACT FROM AUTHOR]

[Display omitted] • IDO1 induces immune tolerance within TME. • Serum profiling of IDO1 metabolites is of prognostic value. • IDO1 upregulation occurs after ICI therapy. • IDO1 inhibitors can be used safely with ICI therapy. • Epacadostat plus ICI renders promising clinical responses. • Clinical efficacy of anti-PD-L1/IDO inhibitor vaccination is promising. Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper. [ABSTRACT FROM AUTHOR]

• A model is proposed based on the key role of Regulatory T cells in chemoimmunotherapy. • The model's fixed points are obtained and the bifurcation diagrams are discussed. • New features of personalizing a cancer mathematical model are presented. • Considering Regulatory T cells leads to identifying critical patient conditions more precisely. Studying the mathematical dynamics of cancer has gained the attention of bioengineers in the past three decades. Different kinds of modelling considering various aspects of treatment have been proposed. In this paper, the key role of Regulatory T cells is discussed and a model in ordinary differential equation (ODE) form is proposed by adding this state to the system dynamics considering chemoimmunotherapy treatment. Regulatory T cells are considered as one of the main tumor cells' tactics to deceive the body's immune system. The improved model is verified mathematically and biologically and fits all criteria in both fields. The results show that entering Regulatory T cells state on cancer mathematical modelling for simulating body cells for chemoimmunotherapy provides a way to identify critical cases more carefully, which a simplified model is unable to accomplish. This point emphasizes the fact that this state must be present in cancer modelling to anticipate immune response more accurately. The advanced system fixed points are obtained by the Newton method and bifurcation diagrams are derived and discussed. New features and remarks are proposed during the journey of developing more accurate models that have the best fit with laboratory data. The sensitivity chart of the model is illustrated and novel aspects of discussions are made with the aim of personalizing a model for a patient and identifying critical conditions based on the chart before any treatment begins. This point enables physicians to determine whether critical conditions have occurred for a patient in a specific treatment or not. [ABSTRACT FROM AUTHOR]

Zukamu granules (ZKMG), as the preferred drug for the treatment of colds in Uygur medical theory, has been used for 1500 years. It is also widely used in China and included in the National Essential Drugs List (2018 edition). It has unique anti-inflammatory, antitussive and analgesic effects. Aiming at the research of traditional Chinese medicine (TCM) with the characteristics of overall regulation of body diseases and the immune regulation mechanism with the concept of integrity, this paper put forward the integrated application of network composite module analysis and animal experiment verification to study the immune regulation mechanism of TCM. The active components and targets of ZKMG were predicted, and network module analysis was performed to explore their potential immunomodulatory mechanisms. Then acute lung injury (ALI) mice and idiopathic pulmonary fibrosis (IPF) rats were used as pathological models to observe the effects of ZKMG on the pathological conditions of infected ALI and IPF rats, determine the contents of Th1, Th2 characteristic cytokines and immunoglobulins, and study the intervention of GATA3/STAT6 signal pathway. The results of network composite module analysis showed that ZKMG contained 173 pharmacodynamic components and 249 potential targets, and four key modules were obtained. The immunomodulatory effects of ZKMG were related to T cell receptor signaling pathway. The validation results of bioeffects that ZKMG could carry out bidirectional immune regulation on Th1/Th2 cytokines in the stage of ALI and IPF, so as to play the role of regulating immune homeostasis and organ protection. The network composite module analysis and verification method is an exploration to study the immune regulation mechanism of TCM by combining the network module prediction analysis with animal experiments, which provides a reference for subsequent research. [Display omitted] [ABSTRACT FROM AUTHOR]

The newly discovered subset of memory T cells, tissue resident memory T (TRM) cells, reside in peripheral tissues for a long time, contributing to a rapid immune response and constituting the first line of defense when pathogens invade cells. Tissue resident memory T cells have unique transcriptome characteristics, and their presence in peripheral tissues is regulated by many factors. TRM cells residing in different tissues often express different surface markers. In addition to CD8+ and CD4+ T cells, which are the best-characterized T cells, Treg cells and various innate T cells can reside in nonlymphoid tissues. Many recent studies have shown that tissue resident memory T cells play indispensable roles in tumor immunity and allergic diseases. This paper reviews the differentiation, regulation, variety and function of TRM cells and the roles they play in skin diseases, including cutaneous melanoma and psoriasis. • Tissue-resident memory T cells exhibit distinct tissue-specific and niche-specific functions in immune detection network. • Multiple factors control the development and resident of Tissue-resident memory T cell. • Tissue-resident memory T cells participate in skin inflammation and contribute tomaintaining the recurrence of skin diseases. [ABSTRACT FROM AUTHOR]

A recent paper by Shi et al. defines the role of regulatory T cells (Tregs) in white matter recovery after ischemic stroke. This study elucidates the mechanisms by which Tregs direct microglia to alter their phenotype to support oligodendrogenesis, thereby improving white matter integrity and functional recovery after stroke in mice. [ABSTRACT FROM AUTHOR]

This paper aimed to explore the roles of the combination of electroacupuncture (EA) and induced pluripotent stem cell-derived small extracellular vesicles (iPSC-EVs) on mice with ischemic stroke and the underlying mechanisms. A focal cerebral ischemia model was established in C57BL/6 mice through middle cerebral artery occlusion (MCAO). After 3 days, neurological impairment and motor function were examined by performing behavioral tests. The infarct volume and neuronal apoptosis were examined using TTC staining and TUNEL assays. Flow cytometry was performed to assess the proliferation of T lymphocytes. The changes in the interleukin (IL)-33/ST2 axis were evaluated by immunofluorescence and Western blotting. The combination of EA and iPSC-EVs treatment ameliorated neurological impairments and reduced the infarct volume and neuronal apoptosis in MCAO mice. EA plus iPSC-EVs suppressed T helper (Th1) and Th17 responses and promoted the regulatory T cell (Treg) response. In addition, EA plus iPSC-EVs exerted neuroprotective effects by regulating the IL-33/ST2 axis and inhibiting the microglia and astrocyte activation. Taken together, the study shows that EA and iPSC-EVs exerted a synergistic neuroprotective effect in MCAO mice, and this treatment may represent a novel potent therapy for ischemic stroke and damage to other tissues. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is classified as the third leading cancer globally and one of the major causes of morbidity and mortality around the world. The interaction of the immune system with the cancer cells plays a vital role in CRC progression. Regulatory T cells (Tregs) are a form of T cells, which regulate and suppress unwanted activation of the immune system and play a major role in preventing autoimmune diseases. Tregs exhibit a significant role in immune modulation during CRC progression through accumulation in the tumor microenvironment (TME) and suppression of immunity against tumor specific antigens promoting tumor progression. The role of Tregs in CRC progression and its interaction with other immune cells within CRC TME and current clinical trials were reviewed in this paper. [Display omitted] • Discusses the role of Tregs in immune modulation during CRC progression. • Explores the role of Tregs in CRC tumor microenvironment. • Highlights the mechanism of Tregs in CRC growth and metastasis. • Identifies and discusses current clinical trials targeting Tregs in CRC therapy. [ABSTRACT FROM AUTHOR]

Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential. [ABSTRACT FROM AUTHOR]