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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]

Summary: Regulatory T cells (Tregs) are a subtype of CD4+ T cells that can mediate immune tolerance by a multitude of immunomodulatory mechanisms. Treg-based adoptive immunotherapy is currently being tested in multiple phases I and II clinical trials in transplantation and autoimmune diseases. We have learned from the work done on conventional T cells that distinct mechanistic states can define their dysfunctions, such as exhaustion, senescence, and anergy. All three can negatively impact the therapeutic effectiveness of T-cell-based therapies. However, whether Tregs are susceptible to such dysfunctional states is not well studied, and results are sometimes found to be controversial. In addition, Treg instability and loss of FOXP3 expression is another Treg-specific dysfunction that can decreasein their suppressive potential. A better understanding of Treg biology and pathological states will be needed to compare and interpret the results of the different clinical and preclinical trials. We will review herein Tregs' mechanisms of action, describe different T-cell dysfunction subtypes and how and if they apply to Tregs (exhaustion, senescence, anergy, and instability), and finally how this knowledge should be taken into consideration when designing and interpreting Treg adoptive immunotherapy trials. Recent advances in Treg-based immunotherapy, as an immune tolerance approach for transplantation and autoimmune diseases, exhibited the need for a better understanding of Treg biology. Classical mechanisms of dysfunction in T cells such as exhaustion, senescence, and anergy are poorly understood in Tregs. Previous works in auto- and alloimmune diseases, as well as in cell-engineering, have shown susceptibility of Tregs to such complications, furthering the importance of this knowledge for future design and interpretation of Treg adoptive immunotherapy trials. [ABSTRACT FROM AUTHOR]

Summary: The Forkhead Box P3 (FOXP3) protein is an essential transcription factor for the development and function of regulatory T cells (Tregs), involved in the maintenance of immunological tolerance. Although extensive research over the last decade has investigated the critical role of FOXP3+ cells in preserving immune homeostasis, our understanding of their specific functions remains limited. Therefore, unveiling the molecular mechanisms underpinning the up- and downstream transcriptional regulation of and by FOXP3 is crucial for developing Treg-targeted therapeutics. Dysfunctions in FOXP3+ Tregs have also been found to be inherent drivers of autoimmune disorders and have been shown to exhibit multifaceted functions in the context of cancer. Recent research suggests that these cells may also be involved in tissue-specific repair and regeneration. Herein, we summarize current understanding of the thymic-transcriptional regulatory landscape of FOXP3+ Tregs, their epigenetic modulators, and associated signaling pathways. Finally, we highlight the contributions of FOXP3 on the functional development of Tregs and reflect on the clinical implications in the context of pathological and physiological immune responses. A subset of CD4+ T cells, recognized as FOXP3+ regulatory T (Treg) cells, are involved in preserving immune tolerance. Defects in these cells drive the pathogenesis of autoimmune diseases. In this review, we discuss the functions and dysfunctions in the developmental pathways of FOXP3+ Tregs, their emerging roles, and explore potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Resveratrol has been reported to reverse the imbalance of T helper 17/regulatory T (Th17/Treg) by inhibiting the aryl hydrocarbon receptor pathway to treat immune thrombocytopenia. However, the regulation mechanism of the Notch signaling pathway by resveratrol has not been reported in purpura. This study is aimed to explore the mechanism of resveratrol ultrafine nanoemulsion (Res-mNE) in immune thrombocytopenia. Methods: The immune thrombocytopenia mouse model was constructed to explore the effect of RES-mNE on immune thrombocytopenia. Cluster of differentiation 4 (CD4+) T cells were isolated and treated with different medications. CD4+ T cells were induced to differentiate into Th17 cells and Treg cells. Flow cytometry was used to detect the proportion of Th17 cells and Treg cells. The secretion was measured by the enzyme-linked immunosorbent assay (ELISA). Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot were used to detect the mRNA and protein levels. Results: Th17 cells, IL-17A and IL-22 increased in the immune thrombocytopenia mouse model, and the Treg cells and IL-10 decreased. Res-mNE promoted Treg cell differentiation and IL-10 secretion in CD4+ T cells while inhibiting Th17 cell differentiation and IL-17A and IL-22 levels. The AhR activator 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reversed the effect of Res-mNE. Notch inhibitors reduced the ratio of Th17/Treg differentiation. Res-mNE activated the expression of Foxp3 by mediating AhR/Notch signaling to reverse the imbalance of Th17/Treg differentiation in immune thrombocytopenia. Conclusion: Taken together, our findings demonstrated that RES-mNE inhibited the AhR/Notch axis and reversed Th17/Treg imbalance by activating Foxp3. [ABSTRACT FROM AUTHOR]

Summary: The actions of the immune system are finely tuned, involving complex communication and coordination between diverse immune and non-immune cells across the tissues of the body. A healthy immune system requires a precise balance between immunity and tolerance. Regulatory T cells (Tregs) have long been appreciated as one of the master regulators of this balance; their importance is underscored by the autoimmunity that develops in mice and humans when Tregs are missing or dysfunctional. In addition to the immunoregulatory roles of Tregs in suppressing autoimmunity and inflammation via control of adaptive and innate immune responses, several non-immune modulatory functions of Tregs have been identified in recent years. In this review, we have highlighted the growing literature on the action of Tregs in metabolism, stem cell maintenance, tissue repair, and angiogenesis. Alongside Tregs' immune suppressive role, these non-suppressive activities comprise a key function of Tregs in regulating health and disease. As Tregs receive increasing attention as therapeutic targets, understanding their non-canonical functions may become an important feature of Treg-directed interventions. Diverse functions of Tregs beyond immune suppression. As detailed in the canonical suppression box, Tregs use several mechanisms to dampen proliferation and function of effector T cells and other immune cells. Tregs also have myriad effects on tissue repair, angiogenesis, basal metabolism, and maintenance of the stem cell niche. [ABSTRACT FROM AUTHOR]

Summary: Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells are a specialized CD4+ T cell subpopulation that are essential for immune homeostasis, immune tolerance, and protection against autoimmunity. There is evidence that sex-steroid hormones estrogen and progesterone modulate Treg cell abundance and phenotype in women. Since natural oscillations in these hormones are modified by hormonal contraceptives, we examined whether oral contraception (OC) use impacts Treg cells and related T cell populations. T cells were analyzed by multiparameter flow cytometry in peripheral blood collected across the menstrual cycle from healthy women either using OC or without hormonal contraception and from age-matched men. Compared to naturally cycling women, women using OC had fewer Treg cells and an altered Treg cell phenotype. Notably, Treg cells exhibiting a strongly suppressive phenotype, defined by high FOXP3, CD25, Helios, HLADR, CTLA4, and Ki67, comprised a lower proportion of total Treg cells, particularly in the early- and mid-cycle phases. The changes were moderate compared to more substantial differences in Treg cells between women and men, wherein women had fewer Treg cells—especially of the effector memory Treg cell subset—associated with more T helper type 1 (Th1) cells and CD8+ T cells and lower Treg:Th1 cell and Treg:CD8+ T cell ratios than men. These findings imply that OC can modulate the number and phenotype of peripheral blood Treg cells and raise the possibility that Treg cells contribute to the physiological changes and altered disease susceptibility linked with OC use. [ABSTRACT FROM AUTHOR]

Although B cells are essential for humoral immunity and show noteworthy immunomodulatory activity through antibody-independent functions, the role of B cells in regulating Treg cell responses remains controversial. Tregs (CD4+CD25+Foxp3+) are considered to play an immunoprotective role in viral myocarditis (VMC) by controlling autoimmune effector T cells. Here, we proved that B-cell knockout can not only lead to significant reductions in Tregs in the spleen, blood, and heart of VMC mice but also decrease the activation and immune function of splenic Tregs, which was reversed by adoptive transfer of B cells; the transcription levels of TGF-β and Foxp3 in the myocardium were also significantly reduced. B-cell depletion by anti-CD20 impaired the anti-inflammatory function of splenic Tregs and the homeostasis of myocardial Tregs population. Moreover, B cells can convert CD4+CD25− T cells into Foxp3+ and Foxp3−, two functionally suppressive Treg subgroups. Although the reduction in myocardial inflammation in BKO mice indicates that B cells may play a proinflammatory role, the beneficial side of B cells cannot be ignored, that is, to control autoimmunity by maintaining Treg numbers. The results observed in the animal model of VMC highlight the potential harm of rituximab in the nonselective depletion of B cells in clinical applications. B cell depletion by anti-CD20 and gene knockout impaired the anti-inflammatory function of splenic Tregs and the homeostasis of myocardial Tregs population in the animal model of VMC. B cells could promote the transformation of Teffs into Foxp3+ and Foxp3-Tregs in vitro. [ABSTRACT FROM AUTHOR]

Background: Although an immunosuppressive tumor microenvironment (TME) is key for tumor progression, the molecular characteristics associated with the immunosuppressive TME remain unknown in triple-negative breast cancer (TNBC). Our previous functional proteomic study of TNBC tumors identified that C-JUN N-terminal kinase (JNK) pathway-related molecules were enriched in a cluster associated with the inflammatory pathway. However, the role of the JNK pathway in the TNBC TME is still unclear.Methods: Transcriptomic analysis was conducted using The Cancer Genome Atlas datasets. The effect of JNK-IN-8, a covalent pan-JNK inhibitor, on TNBC tumor growth, lung metastasis, and the TME was measured in TNBC syngeneic mouse models (n = 13 per group). Tumor (n = 43) or serum (n = 46) samples from TNBC patients were analyzed using multiplex immunohistochemistry or Luminex assay. All statistical tests were 2-sided.Results: CIBERSORT analysis revealed that TNBC patients with high phosphorylated JNK level (n = 47) had more regulatory T cell (Treg) infiltration than those with a low phosphorylated JNK level (n = 47) (P = .02). Inhibition of JNK signaling statistically significantly reduced tumor growth (P < .001) and tumor-infiltrating Tregs (P = .02) while increasing the infiltration of CD8+ T cells in TNBC mouse models through the reduction of C-C motif ligand 2 (CCL2). Tumor-associated macrophages were the predominant cells secreting CCL2, and inhibition of JNK signaling reduced CCL2 secretion of human primary macrophages. Moreover, in patients with TNBC (n = 43), those with high levels of CCL2+ tumor-associated macrophages had more Treg and less CD8+ T cell infiltration (P = .04), and the serum CCL2 level was associated with poor overall survival (hazard ratio = 2.65, 95% confidence interval = 1.29 to 5.44, P = .008) in TNBC patients (n = 46).Conclusions: The JNK/C-JUN/CCL2 axis contributes to TNBC aggressiveness via forming an immunosuppressive TME and can offer novel therapeutic strategies for TNBC. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with impaired immune function and chronic low-grade inflammation. Metabolic surgery is one of the most effective therapies for treating obesity and related metabolic disorders. We aimed to explore the pathophysiological roles of peripheral dendritic cells (DCs) and T lymphocytes in metabolic surgery. Method: In this observational cohort study, a total of 106 individuals, including obese participants with or without T2DM, overweight subjects and normal controls, were recruited. All obese participants underwent laparoscopic sleeve gastrectomy surgery and returned for the evaluation of the clinical indicators after surgery. We evaluated the frequencies of circulating DCs subsets (myeloid (mDCs) and plasmacytoid (pDCs)), the pro-inflammatory (Th1 and I Th17) and anti-inflammatory (Th2 and Treg) T cell subsets by flow cytometry. Results: Compared with normal controls, the frequencies of mDCs, Th1 and Th17 cells increased, while Treg and Th2 cells decreased in the obese participants. The frequency of mDCs and Th1 cells consistently declined after surgery compared with baseline in the obese patients and were restored to the levels observed in the normal controls after surgery. Moreover, the frequency of Treg cells was increased at 6 months after surgery in the obese patients with T2DM, and Th17 cells declined at 6 months after surgery in the severely obese patients without T2DM. Conclusion: This study indicates that metabolic surgery can effectively improve imbalanced immune cells in peripheral blood and restore the proportion of immune cells to a normal range during a 12-month follow-up. [ABSTRACT FROM AUTHOR]

The mechanism of antigen‐specific regulatory T cell (Treg) induction is not yet fully understood. Curcumin has an immune regulatory function. This study aims to induce antigen‐specific Tregs by employing extracellular vesicles (EVs) that carry two types of T cell activators. Two types of T cell activators, ovalbumin (OVA)/major histocompatibility complex‐II (MHC‐II) and tetramethylcurcumin (FLLL31) (a curcumin analog) were carried by dendritic cell‐derived extracellular vesicles, designated OFexo. A murine model of allergic rhinitis (AR) was developed with OVA as the specific antigen. AR mice were treated with a nasal instillation containing OFexo. We observed that OFexo recognized antigen‐specific T cell receptors (TCR) on CD4+ T cells and enhanced Il10 gene transcription in CD4+ T cells. Administration of the OFexo‐containing nasal instillation induced antigen‐specific type 1 Tregs (Tr1 cells) in the mouse airway tissues. OFexo‐induced Tr1 cells showed immune suppressive functions on CD4+ T cell proliferation. Administration of OFexo efficiently alleviated experimental AR in mice. In conclusion, OFexo can induce antigen‐specific Tr1 cells that can efficiently alleviate experimental AR. The results suggest that OFexo has the translational potential to be employed for the treatment of AR or other allergic disorders. [ABSTRACT FROM AUTHOR]