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Future study should focus on the further understanding of molecular mechanism underlying Treg-stimulatory effect of TNFR2 signal, as well as on the translation of research findings into therapeutic benefits of human patients with autoimmune diseases, allergy, allograft rejection, and cancer.Regulatory T cells (Tregs) are critical in maintaining immune homeostasis under various pathophysiological conditions. A growing body of evidence demonstrates that Tregs play an important role in cancer progression and that they do so by suppressing cancer-directed immune responses. Tregs have been targeted for destruction by exploiting antibodies against and small-molecule inhibitors of several molecules that are highly expressed in Tregs-including immune checkpoint molecules, chemokine receptors, and metabolites. To date, these strategies have had only limited antitumor efficacy, yet they have also created significant risk of autoimmunity because most of them do not differentiate Tregs in tumors from those in normal tissues. Currently, immune checkpoint inhibitor (ICI)-based cancer immunotherapies have revolutionized cancer treatment, but the resistance to ICI is common and the elevation of Tregs is one of the most important mechanisms. Therapeutic strategies that can selectively eliminate Tregs in the tumor (i.e. therapies that do not run the risk of causing autoimmunity by affecting normal tissue), are urgently needed for the development of cancer immunotherapies. This chapter discusses specific properties of human Tregs under the context of cancer and the various ways to target Treg for cancer immunotherapy.Uveitis is a chronic disease with relapsing and remitting ocular attack, which requires corticosteroids and systemic immunosuppression to prevent severe vision loss. Classically, uveitis is referred to an autoimmune disease, mediated by pro-inflammatory Th17 cells and immunosuppressive CD4+CD25+FoxP3+ T-regulatory cells (Tregs). More and more evidence indicates that Tregs are involved in development, resolution, and remission of uveitis. Clinically, many researchers have conducted quantitative and functional analyses of peripheral blood from patients with different subtypes of uveitis, in an attempt to find the changing rules of Tregs. Consistently, using the experimental autoimmune uveitis (EAU) model, researchers have explored the development and resolution mechanism of uveitis in many aspects. In addition, many drug and Tregs therapy investigations have yielded encouraging results. In this chapter, we introduced the current understanding of Tregs, summarized the clinical changes in the number and function of patients with uveitis and the immune mechanism of Tregs involved in EAU model, as well as discussed the progress and shortcomings of Tregs-related drug therapy and Tregs therapy. https://www.selleckchem.com/btk.html Although the exact mechanism of Tregs-mediated uveitis protection remains to be elucidated, the strategy of Tregs regulation may provide a specific and meaningful way for the prevention and treatment of uveitis.Autoimmune conditions affect 23 million Americans or 7% of the US population. There are more than 100 autoimmune disorders, affecting every major organ system in humans. This chapter aims to further explain Treg dysfunction autoimmune disorders, including monogenic primary immune deficiency such as immune dysregulation polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome, and polygenic autoimmune diseases with Treg dysfunction such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and food allergy. These conditions are associated with an abnormal small intestinal and colonic microbiome. Some disorders clearly improve with therapies aimed at microbial modification, including probiotics and fecal microbiota transplantation (FMT). Approaches to prevent and treat these disorders will need to focus on the acquisition and maintenance of a healthy colonic microbiota, in addition to more focused approaches at immune suppression during acute disease exacerbations.Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.Obesity dramatically increases the risk of numerous conditions, including type 2 diabetes mellitus and other components of the metabolic syndrome. Pro-inflammatory changes that occur in adipose tissue are critical to the pathogenesis of these obesity-induced complications. Adipose tissue is one of the body's largest endocrine organs, and the cells that comprise the adipose tissue immunoenvironment secrete multiple factors (including adipokines and cytokines) that impact systemic metabolism. In particular, immunosuppressive regulatory T cells (Tregs) decline in obesity, partly in response to its complex interaction with adipocytes, and this decline contributes to disruption of the typical homeostasis observed in lean adipose tissue. Although the regulation of Treg differentiation, function, and enrichment is incompletely understood, factors including various cell-surface co-stimulatory molecules, certain lipid species, and cytokines such as PPARγ, adiponectin, and leptin are important mediators. It is also clear that there may be depot-specific differences in Tregs, rendering adipose tissue Tregs distinct from lymphoid or circulating Tregs, with implications on maintenance and functionality.