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Autoimmune diseases result from imbalances in the immune system and disturbances in the mechanisms of immune tolerance. T-regulatory cells (Treg) are key factors in the formation of immune tolerance. Tregs modulate immune responses and repair processes, controlling the innate and adaptive immune system. The use of Tregs in the treatment of autoimmune diseases began with the manipulation of endogenous Tregs using immunomodulatory drugs. Then, a method of adoptive transfer of Tregs grown in vitro was developed. Adoptive transfer of Tregs includes polyclonal Tregs with non-specific effects and antigen-specific Tregs in the form of CAR-Treg and TCR-Treg. This review discusses non-specific and antigen-specific approaches to the use of Tregs, their advantages, disadvantages, gaps in development, and future prospects. [ABSTRACT FROM AUTHOR]

Purposes: Previous studies have demonstrated that proliferation, stroma or immunity strongly influence the prognosis and therapeutic resistance of diffuse large B-cell lymphoma (DLBCL). Herein, we aimed to integrate proliferation, stromal, and immune (PSI) features to systematically evaluate the risk stratification and explore novel therapeutic targets in DLBCL. Methods: Using data from multiple researches, we comprehensively evaluated the characteristics and prognostic impact of PSI features in DLBCL, and developed a novel risk stratification model (PSI score) with a consistent cutoff value to stratify the risk of 3,229 DLBCL patients from different cohorts. Mechanisms underlying adverse prognosis in the high-risk DLBCLs were investigated through transcriptomic (n = 3,229), genomic (n = 576), and scRNA-seq (n = 20) analyses. Results: We identified a high-risk DLBCL subgroup (HPSI, 36.1% of DLBCL). HPSI was characterized by upregulation of spermidine synthase (SRM) and cold tumor microenvironment (TME). Compared to low-risk group, HPSI exhibited poorer prognosis, with lower 3-year OS (51.7% vs. 78.1%, P < 0.0001) and PFS (48.9% vs. 72.6%, P < 0.0001) rates. HPSI shared malignant proliferative phenotype resembling Burkitt lymphoma. Genomic analysis revealed extensive copy-number loss in the chemokine and interleukin coding regions within HPSI. Bulk and scRNA-seq analyses indicated that upregulation of SRM might mediate cold TME in DLBCL, potentially through suppressing immune activation pathways, promoting dendritic cells (DCs) transformation into tolerogenic DCs, and facilitating M2 polarization of macrophages. Finally, for eventual clinical translation, we integrated the model with other clinical features to develop a comprehensive database for DLBCL. Conclusion: Our study effectively simplifies risk stratification of DLBCL, revealing that immune microenvironment and SRM jointly shape a subgroup of DLBCL with extremely poor prognosis. Targeting SRM may become a potential strategy for modulating immunotherapy in DLBCL, providing new insight for immunotherapy. [ABSTRACT FROM AUTHOR]

Vaccines represent an essential tool for the prevention of infectious diseases. Upon administration, a complex interaction occurs between the vaccine formulation and the recipient's immune system, ultimately resulting in protection against disease. Significant variability exists in individual and population responses to vaccination, and these differences remain the focus of the ongoing research. Notably, well-documented factors, such as age, gender, and genetic predisposition, influence immune responses. In contrast, the effects of overweight and obesity have not been as thoroughly investigated. The evidence indicates that a high body mass index (BMI) constitutes a significant risk factor for infections in general, with adipose tissue playing a crucial role in modulating the immune response. Furthermore, suboptimal levels of vaccine seroconversion have been observed among individuals with obesity. This review provides a plausible examination of the immunity and protection conferred by various vaccines in individuals with an overweight status, offering a comprehensive analysis of the mechanisms to enhance vaccination efficiency. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group of T lymphocytes with the ability to suppress immune responses and maintain immune homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity and facilitate cancer progression by weakening functions of effector T cells (Teffs). Consequently, targeting Tregs to eliminate them from tumor microenvironments to improve Teffs' activity could emerge as an effective strategy for cancer immunotherapy. This review outlines the biology of Tregs, detailing their origins, classification, and crucial markers. Our focus lies on the complex role of Tregs in cancer's development, progression and treatment, particularly on their suppressive role upon antitumor responses via multiple mechanisms. We delve into Tregs' involvement in immune checkpoint blockade (ICB) therapy, their dual effect on cancer immunotherapy and their potential biomarkers for ICB therapy effectiveness. We also summarize advances in the therapies that adjust Tregs to optimize ICB therapy, which may be crucial for devising innovative cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a leading cause of cancer-related mortality globally, with most patients diagnosed at advanced stages and facing limited early treatment options. This study aimed to identify characteristic genes associated with T-cell exhaustion due to senescence in hepatocellular carcinoma patients, elucidating the interplay between senescence and T-cell exhaustion. We constructed prognostic models based on five signature genes (ENO1, STMN1, PRDX1, RAN, and RANBP1) linked to T-cell exhaustion, utilizing elastic net regression. The findings indicate that increased expression of ENO1 in T cells may contribute to T-cell exhaustion and Treg infiltration in hepatocellular carcinoma. Furthermore, molecular docking was employed to screen small molecule compounds that target the anti-tumor effects of these exhaustion-related genes. This study provides crucial insights into the diagnosis and treatment of hepatocellular carcinoma, establishing a strong foundation for the development of predictive biomarkers and therapeutic targets for affected patients. [ABSTRACT FROM AUTHOR]

TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. However, emerging evidence indicates that TRAIL can also trigger a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, an increasing number of studies suggest that in some circumstances TRAIL can induce, via Death receptor 5 (DR5), tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. In this study, we the current state of knowledge of TRAIL non-canonical signalling. [ABSTRACT FROM AUTHOR]

Simple Summary: Adoptive immunotherapy has emerged as an effective alternative of mounting impact to the current standard of care in cancer, viral infections, and recently, autoimmunity. Key players in maintaining immune homeostasis are the regulatory T cells (Tregs), a major immunosuppressive cell subset and, therefore, an attractive candidate for the cellular therapy of autoimmune disorders or allo-responses in the transplantation setting. Notwithstanding the safety and tolerability of Tregs in early trials, their efficacy remains rather ill-defined, being limited by poor persistence and a lack of specificity, thus hindering widespread clinical application. However, the better biological understanding of in vivo Treg performance and the recent advances in genetic engineering have led to the next-generation Treg immunotherapy era, enabling the introduction of new features in Tregs and generating more potent and targeted Treg cellular therapies. In this review, we discuss the current achievements and existing challenges towards clinically translating Tregs into a living drug therapy for a variety of inflammatory conditions. Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and homeostasis. The unique ability to regulate aberrant immune responses has generated the concept of harnessing Tregs as a new cellular immunotherapy approach for reshaping undesired immune reactions in autoimmune diseases and allo-responses in transplantation to ultimately re-establish tolerance. However, a number of issues limit the broad clinical applicability of Treg adoptive immunotherapy, including the lack of antigen specificity, heterogeneity within the Treg population, poor persistence, functional Treg impairment in disease states, and in vivo plasticity that results in the loss of suppressive function. Although the early-phase clinical trials of Treg cell therapy have shown the feasibility and tolerability of the approach in several conditions, its efficacy has remained questionable. Leveraging the smart tools and platforms that have been successfully developed for primary T cell engineering in cancer, the field has now shifted towards "next-generation" adoptive Treg immunotherapy, where genetically modified Treg products with improved characteristics are being generated, as regards antigen specificity, function, persistence, and immunogenicity. Here, we review the state of the art on Treg adoptive immunotherapy and progress beyond it, while critically evaluating the hurdles and opportunities towards the materialization of Tregs as a living drug therapy for various inflammation states and the broad clinical translation of Treg therapeutics. [ABSTRACT FROM AUTHOR]

Replacement of diseased organs with transplanted healthy donor ones remains the best and often only treatment option for end-stage organ disease. Immunosuppressants have decreased the incidence of acute rejection, but long-term survival remains limited. The broad action of current immunosuppressive drugs results in global immune impairment, increasing the risk of cancer and infections. Hence, achievement of allograft tolerance, in which graft function is maintained in the absence of global immunosuppression, has long been the aim of transplant clinicians and scientists. Regulatory T cells (Treg) are a specialized subset of immune cells that control a diverse array of immune responses, can prevent allograft rejection in animals, and have recently been explored in early phase clinical trials as an adoptive cellular therapy in transplant recipients. It has been established that allograft residency by Tregs can promote graft acceptance, but whether intragraft Treg functional diversification and spatial organization contribute to this process is largely unknown. In this review, we will explore what is known regarding the properties of intragraft Tregs during allograft acceptance and rejection. We will summarize recent advances in understanding Treg tissue residency through spatial, transcriptomic and high-dimensional cytometric methods in both animal and human studies. Our discussion will explore properties of intragraft Tregs in mediating operational tolerance to commonly transplanted solid organs. Finally, given recent developments in Treg cellular therapy, we will review emerging knowledge of whether and how these adoptively transferred cells enter allografts in humans. An understanding of the properties of intragraft Tregs will help lay the foundation for future therapies that will promote immune tolerance. [ABSTRACT FROM AUTHOR]

The Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) is a cutting-edge technology that enables researchers to assess genome-wide chromatin accessibility and to characterize cell type specific gene-regulatory programs. Recent technological progress allows for using this technology also on the single-cell level. In this article, we describe the whole value chain from the isolation of T cells from murine tissues to a complete bioinformatic analysis workflow. We start with methods for isolating scATAC-seq-ready CD4+ T cells from murine tissues such as visceral adipose tissue, skin, colon, and secondary lymphoid tissues such as the spleen. We describe the preparation of nuclei and quality control parameters during library preparation. Based on publicly available sequencing data that was generated using these protocols, we describe a step-by-step bioinformatic analysis pipeline for data pre-processing and downstream analysis. Our analysis workflow will follow the R-based bioinformatics framework ArchR, which is currently well established for scATAC-seq datasets. All in all, this work serves as a one-stop shop for generating and analyzing chromatin accessibility landscapes in T cells. [ABSTRACT FROM AUTHOR]

Single-cell gene expression analysis using sequencing (scRNA-seq) has gained increased attention in the past decades for studying cellular transcriptional programs and their heterogeneity in an unbiased manner, and novel protocols allow the simultaneous measurement of gene expression, T-cell receptor clonality and cell surface protein expression. In this article, we describe the methods to isolate scRNA/TCR-seq-compatible CD4+ T cells from murine tissues, such as skin, spleen, and lymph nodes. We describe the processing of cells and quality control parameters during library preparation, protocols for multiplexing of samples, and strategies for sequencing. Moreover, we describe a step-by-step bioinformatic analysis pipeline from sequencing data generated using these protocols. This includes quality control, preprocessing of sequencing data and demultiplexing of individual samples. We perform quantification of gene expression and extraction of T-cell receptor alpha and beta chain sequences, followed by quality control and doublet detection, and methods for harmonization and integration of datasets. Next, we describe the identification of highly variable genes and dimensionality reduction, clustering and pseudotemporal ordering of data, and we demonstrate how to visualize the results with interactive and reproducible dashboards. We will combine different analytic R-based frameworks such as Bioconductor and Seurat, illustrating how these can be interoperable to optimally analyze scRNA/TCR-seq data of CD4+ T cells from murine tissues. [ABSTRACT FROM AUTHOR]

As the body's integumentary system, the skin is vulnerable to injuries. The subsequent wound healing processes aim to restore dermal and epidermal integrity and functionality. To this end, multiple tissue-resident cells and recruited immune cells cooperate to efficiently repair the injured tissue. Such temporally- and spatially-coordinated interplay necessitates tight regulation to prevent collateral damage such as overshooting immune responses and excessive inflammation. In this context, regulatory T cells (Tregs) hold a key role in balancing immune homeostasis and mediating cutaneous wound healing. A comprehensive understanding of Tregs' multifaceted field of activity may help decipher wound pathologies and, ultimately, establish new treatment modalities. Herein, we review the role of Tregs in orchestrating the regeneration of skin adnexa and catalyzing healthy wound repair. Further, we discuss how Tregs operate during fibrosis, keloidosis, and scarring. [ABSTRACT FROM AUTHOR]

Mucosal barrier integrity and pathogen clearance is a complex process influenced by both Th17 and Treg cells. Previously, we had described the DNA methylation profile of Th17 cells and identified Zinc finger protein (Zfp)362 to be uniquely demethylated. Here, we generated Zfp362−/− mice to unravel the role of Zfp362 for Th17 cell biology. Zfp362−/− mice appeared clinically normal, showed no phenotypic alterations in the T‐cell compartment, and upon colonization with segmented filamentous bacteria, no effect of Zfp362 deficiency on Th17 cell differentiation was observed. By contrast, Zfp362 deletion resulted in increased frequencies of colonic Foxp3+ Treg cells and IL‐10+ and RORγt+ Treg cell subsets in mesenteric lymph nodes. Adoptive transfer of naïve CD4+ T cells from Zfp362−/− mice into Rag2−/− mice resulted in a significantly lower weight loss when compared with controls receiving cells from Zfp362+/+ littermates. However, this attenuated weight loss did not correlate with alterations of Th17 cells but instead was associated with an increase of effector Treg cells in mesenteric lymph nodes. Together, these results suggest that Zfp362 plays an important role in promoting colonic inflammation; however, this function is derived from constraining the effector function of Treg cells rather than directly promoting Th17 cell differentiation. [ABSTRACT FROM AUTHOR]

Maintenance of peripheral tolerance by CD4+Foxp3+ regulatory T cells (Tregs) is essential for regulating autoreactive T cells. The loss of function of Foxp3 leads to autoimmune disease in both animals and humans. An example is the rare, Xlinked recessive disorder known as IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked) syndrome. In more common human autoimmune diseases, defects in Treg function are accompanied with aberrant effector cytokines such as IFNγ. It has recently become appreciated that Tregs plays an important role in not only maintaining immune homeostasis but also in establishing the tissue microenvironment and homeostasis of nonlymphoid tissues. Tissue resident Tregs show profiles that are unique to their local environments which are composed of both immune and non-immune cells. Core tissue-residence gene signatures are shared across different tissue Tregs and are crucial to homeostatic regulation and maintaining the tissue Treg pool in a steady state. Through interaction with immunocytes and nonimmunocytes, tissue Tregs exert a suppressive function via conventional ways involving contact dependent and independent processes. In addition, tissue resident Tregs communicate with other tissue resident cells which allows Tregs to adopt to their local microenvironment. These bidirectional interactions are dependent on the specific tissue environment. Here, we summarize the recent advancements of tissue Treg studies in both human and mice, and discuss the molecular mechanisms that maintain tissue homeostasis and prevent pathogenesis. [ABSTRACT FROM AUTHOR]

Regulatory T cells in non-lymphoid tissues are not only critical for maintaining self-tolerance, but are also important for promoting organ homeostasis and tissue repair. It is proposed that the generation of tissue Treg cells is a stepwise, multi-site process, accompanied by extensive epigenome remodeling, finally leading to the acquisition of unique tissue-specific epigenetic signatures. This process is initiated in the thymus, where Treg cells acquire core phenotypic and functional properties, followed by a priming step in secondary lymphoid organs that permits Treg cells to exit the lymphoid organs and seed into non-lymphoid tissues. There, a final specialization process takes place in response to unique microenvironmental cues in the respective tissue. In this review, we will summarize recent findings on this multi-site tissue Treg cell differentiation and highlight the importance of epigenetic remodeling during these stepwise events. [ABSTRACT FROM AUTHOR]

Background: Technical improvement in ATAC-seq makes it possible for high throughput profiling the chromatin states of single cells. However, data from multiple sources frequently show strong technical variations, which is referred to as batch effects. In order to perform joint analysis across multiple datasets, specialized method is required to remove technical variations between datasets while keep biological information. Results: Here we present an algorithm named epiConv to perform joint analyses on scATAC-seq datasets. We first show that epiConv better corrects batch effects and is less prone to over-fitting problem than existing methods on a collection of PBMC datasets. In a collection of mouse brain data, we show that epiConv is capable of aligning low-depth scATAC-Seq from co-assay data (simultaneous profiling of transcriptome and chromatin) onto high-quality ATAC-seq reference and increasing the resolution of chromatin profiles of co-assay data. Finally, we show that epiConv can be used to integrate cells from different biological conditions (T cells in normal vs. germ-free mouse; normal vs. malignant hematopoiesis), which reveals hidden cell populations that would otherwise be undetectable. Conclusions: In this study, we introduce epiConv to integrate multiple scATAC-seq datasets and perform joint analysis on them. Through several case studies, we show that epiConv removes the batch effects and retains the biological signal. Moreover, joint analysis across multiple datasets improves the performance of clustering and differentially accessible peak calling, especially when the biological signal is weak in single dataset. [ABSTRACT FROM AUTHOR]

Treg cells have been initially described as gatekeepers for the control of autoimmunity, as they can actively suppress the activity of other immune cells. However, their role goes beyond this as Treg cells further control immune responses during infections and tumor development. Furthermore, Treg cells can acquire additional properties for e.g., the control of tissue homeostasis. This is instructed by a specific differentiation program and the acquisition of effector properties unique to Treg cells in non-lymphoid tissues. These tissue Treg cells can further adapt to their tissue environment and acquire distinct functional properties through specific transcription factors activated by a combination of tissue derived factors, including tissue-specific antigens and cytokines. In this review, we will focus on recent findings extending our current understanding of the role and differentiation of these tissue Treg cells. As such we will highlight the importance of tissue Treg cells for tissue maintenance, regeneration, and repair in adipose tissue, muscle, CNS, liver, kidney, reproductive organs, and the lung. [ABSTRACT FROM AUTHOR]

Regulator T cells (Tregs) play pivotal roles in maintaining immune tolerance and regulating immune responses against pathogens and tumors. Reprogramming of cellular metabolism has been determined as a crucial process that connects microenvironmental cues and signaling networks to influence homeostasis and function of tissue Tregs. In adaptation to a variety of non-lymphoid tissues, Tregs coordinate local immune signals and signaling networks to rewire cellular metabolic programs to sustain their suppressive function. Altered Treg metabolism in turn shapes Treg activation and function. In light of the advanced understanding of immunometabolism, manipulation of systemic metabolites has been emerging as an attractive strategy aiming to modulate metabolism and function of tissue Tregs and improve the treatment of immune-related diseases. In this review, we summarize key immune signals and metabolic programs involved in the regulation of tissue Tregs, review the mechanisms underlying the differentiation and function of Tregs in various non-lymphoid tissues, and discuss therapeutic intervention of metabolic modulators of tissue Tregs for the treatment of autoimmune diseases and cancer. [ABSTRACT FROM AUTHOR]

The literature surrounding KLRG1 has primarily focused on NK and CD8+ T cells. However, there is evidence that the most suppressive Tregs express KLRG1. Until now, the role of KLRG1 on Tregs has been mostly overlooked and remains to be elucidated. Here we review the current literature on KLRG1 with an emphasis on the KLRG1+ Treg subset role during cancer development and autoimmunity. KLRG1 has been recently proposed as a new checkpoint inhibitor target, but these studies focused on the effects of KLRG1 blockade on effector cells. We propose that when designing anti-tumor therapies targeting KLRG1, the effects on both effector cells and Tregs will have to be considered. [ABSTRACT FROM AUTHOR]

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer‐reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state‐of‐the‐art handbook for basic and clinical researchers. [ABSTRACT FROM AUTHOR]

Forkhead box protein 3 (Foxp3+)-expressing regulatory T (Treg) cells are a unique CD4+T cell subset that suppresses excessive immune responses. The epigenetic plasticity and metabolic traits of Treg cells are crucial for the acquisition of their phenotypic and functional characteristics. Therefore, alterations to the epigenetics and metabolism affect Treg cell development and function. Recent evidence reveals that altering the metabolic pathways and generation of metabolites can regulate the epigenetics of Treg cells. Specifically, some intermediates of cell metabolism can directly act as substrates or cofactors of epigenetic-modifying enzymes. Here, we describe the metabolic and epigenetic features during Treg cell development, and discuss how metabolites can contribute to epigenetic alterations of Treg cells, which affects Treg cell activation, differentiation, and function. [ABSTRACT FROM AUTHOR]