Regulatory T cells in the treatment of disease.
Sharabi Amir,Tsokos Maria G,Ding Ying,Malek Thomas R,Klatzmann David,Tsokos George C
Nature reviews. Drug discovery
Regulatory T (T) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, T cells are compromised. Approaches to strengthen T cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing T cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, T cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of T cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating T cells in autoimmune disorders, transplantation and cancer.
Harnessing regulatory T cells for the treatment of inflammatory bowel disease.
Geem Duke,Harusato Akihito,Flannigan Kyle,Denning Timothy L
Inflammatory bowel diseases
Regulatory CD4 T (Treg) cells are comprised of a heterogeneous population of cells that play a vital role in suppressing inflammation and maintaining immune tolerance. The immunoregulatory function of Treg cells is especially important in the intestine where the mucosa is exposed to a diverse array of foreign antigens-including those derived from food and commensal bacteria. Treg cells are enriched in the intestinal lamina propria and provide a crucial function in promoting tolerance to enteric antigens while modulating tissue inflammation. Correspondingly, Treg cell dysfunction is associated with a breakdown in intestinal tolerance and the induction of aberrant immune responses that may contribute to the pathogenesis of inflammatory bowel disease. This review will provide a brief overview of Treg cell biology with a focus on Foxp3 Treg and type 1 regulatory (Tr1) cells and summarize the evidence for defective Treg cells in experimental and human inflammatory bowel disease. The potential application of Treg cells as a treatment for inflammatory bowel disease will also be discussed in the context of Treg infusion therapy and the in vivo induction/expansion of intestinal Treg cells.
Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells.
Chien Chien-Hui,Chiang Bor-Luen
Journal of biomedical science
Regulatory T cells play a crucial role in the homeostasis of the immune response. In addition to CD4Foxp3 regulatory T cells, several subsets of Foxp3 regulatory T cells, such as T helper 3 (Th3) cells and type 1 regulatory T (Tr1) cells, have been described in mice and human. Accumulating evidence shows that naïve B cells contribute to tolerance and are able to promote regulatory T cell differentiation. Naïve B cells can convert CD4CD25 T cells into CD25Foxp3 regulatory T cells, named Treg-of-B cells by our group. Treg-of-B cells express LAG3, ICOS, GITR, OX40, PD1, and CTLA4 and secrete IL-10. Intriguingly, B-T cell-cell contact but not IL-10 is essential for Treg-of-B cells induction. Moreover, Treg-of-B cells possess both IL-10-dependent and IL-10-independent inhibitory functions. Treg-of-B cells exert suppressive activities in antigen-specific and non-antigen-specific manners in vitro and in vivo. Here, we review the phenotype and function of Foxp3 regulatory T cells, Th3 cells, Tr1 cells, and Treg-of-B cells.
IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes.
Apert Cécile,Romagnoli Paola,van Meerwijk Joost P M
Protein & cell
Immunosuppressive regulatory T lymphocytes (Treg) expressing the transcription factor Foxp3 play a vital role in the maintenance of tolerance of the immune-system to self and innocuous non-self. Most Treg that are critical for the maintenance of tolerance to self, develop as an independent T-cell lineage from common T cell precursors in the thymus. In this organ, their differentiation requires signals from the T cell receptor for antigen, from co-stimulatory molecules, as well as from cytokine-receptors. Here we focus on the cytokines implicated in thymic development of Treg, with a particular emphasis on the roles of interleukin-2 (IL-2) and IL-15. The more recently appreciated involvement of TGF-β in thymic Treg development is also briefly discussed. Finally, we discuss how cytokine-dependence of Treg development allows for temporal, quantitative, and potentially qualitative modulation of this process.
Transcriptional regulation and development of regulatory T cells.
Lee Wonyong,Lee Gap Ryol
Experimental & molecular medicine
Regulatory T (Treg) cells are a distinct subset of CD4 T cells. Instead of triggering adaptive immunity, they suppress immune responses. Small numbers of Treg cells reside within lymphoid organs and peripheral tissues, but their contribution to immune tolerance is so significant that defects in Treg cell function cause catastrophic immune disorders. Since they were first discovered 20 years ago, efforts have been made to understand the differences in developmental processes between Treg cells and conventional T cells that determine the ultimate fate of the overall T-cell population. Transcription factor Foxp3 is crucial for Treg cell differentiation, but it is not the whole story. Owing to recent advances in Treg cell research, we are now on the verge of appreciating the comprehensive mechanisms underlying Treg cell generation. Here, we discuss major discoveries, active study topics and remaining questions regarding Treg cell development.
Foxp3 T Regulatory Cells: Still Many Unanswered Questions-A Perspective After 20 Years of Study.
Shevach Ethan M
Frontiers in immunology
T regulatory (Treg) cells were discovered more than 20 years ago and have remained a topic of intense investigation by immunologists. The initial doubts about their existence were dissipated by the discovery in 2003 of the lineage specific transcription factor Foxp3. In this article, I will discuss some of the questions that I believe still need to be answered before we will be able to fully apply Treg therapy to the clinic. The major issue that remains to be resolved is how they mediate their suppressive functions. In order to correct defective suppression in autoimmune disease (assuming it is a causative factor) or to augment suppression in graft versus host disease or during organ transplantation, we still need to fully understand the biochemical nature of suppressor mechanisms. Similarly, in cancer, it is now widely accepted that reversal of Treg suppression would be highly desirable, yet which of the many purported pathways of suppression are operative in different tumors in different anatomic sites. Many of the concepts we have developed are based on studies, and it remains unclear if these concepts can readily be applied to Treg function . Our lack of a specific cell surface marker that readily allows us to identify and target Treg , particularly in man, remains a major stumbling block. Finally, I will review in some detail controversies regarding the origin of Treg, thymus versus periphery, and attempts to reverse Treg suppression by targeting antigens on their cell surface, particularly members of the TNF receptor superfamily. Hopefully, these areas of controversy will be resolved by in depth studies over the next few years and manipulation of Treg function will be placed on a more solid experimental footing.
Overview of LAG-3-Expressing, IL-10-Producing Regulatory T Cells.
Fujio Keishi,Yamamoto Kazuhiko,Okamura Tomohisa
Current topics in microbiology and immunology
Regulatory T cells (Treg cells) play crucial roles in the induction of peripheral tolerance to self- and foreign-antigens. IL-10-producing regulatory T cells (IL-10-producing Treg cells) constitute a Treg cell subset characterized by the production of high amounts of IL-10, cytokine-mediated immunosuppressive capabilities, and independence of Foxp3 expression for their suppressive activity. In the past decade, identifying naturally occurring IL-10-producing Treg cells was difficult due to the lack of suitable surface markers. More recently, lymphocyte activation gene 3 (LAG-3) is a CD4 homologue that has been identified as a marker for IL-10-producing Treg cells. CD4CD25LAG3 T cells produce large amounts of IL-10 and suppress colitis in a mouse model. These CD4CD25LAG3 Treg cells also exhibit suppressive activity in murine models of lupus and humoral immunity in a TGF-β3-dependent manner. Moreover, the combined expression of LAG-3 and CD49b identifies IL-10-producing Treg cells in mice and humans more specifically. Recently, LAG-3 has gained more attention in the context of immune checkpoints because it believed to be related to T cell tolerance and exhausted T cells that infiltrate the tumor microenvironment. Tumors and the tumor microenvironment promote development of IL-10-producing Treg cells and foster tumor growth. This response might interfere with protective immune responses. Understanding LAG-3-expressing IL-10-producing Treg cells may contribute to the development of novel therapeutic strategies in immune-mediated diseases.
Regulatory T cells in cardiovascular diseases.
Meng Xiao,Yang Jianmin,Dong Mei,Zhang Kai,Tu Eric,Gao Qi,Chen Wanjun,Zhang Cheng,Zhang Yun
Nature reviews. Cardiology
Inflammation is essential in the initial development and progression of many cardiovascular diseases involving innate and adaptive immune responses. The role of CD4(+)CD25(+)FOXP3(+) regulatory T (TREG) cells in the modulation of inflammation and immunity has received increasing attention. Given the important role of TREG cells in the induction and maintenance of immune homeostasis and tolerance, dysregulation in the generation or function of TREG cells can trigger abnormal immune responses and lead to pathology. A wealth of evidence from experimental and clinical studies has indicated that TREG cells might have an important role in protecting against cardiovascular disease, in particular atherosclerosis and abdominal aortic aneurysm. In this Review, we provide an overview of the roles of TREG cells in the pathogenesis of a number of cardiovascular diseases, including atherosclerosis, hypertension, ischaemic stroke, abdominal aortic aneurysm, Kawasaki disease, pulmonary arterial hypertension, myocardial infarction and remodelling, postischaemic neovascularization, myocarditis and dilated cardiomyopathy, and heart failure. Although the exact molecular mechanisms underlying the cardioprotective effects of TREG cells are still to be elucidated, targeted therapies with TREG cells might provide a promising and novel future approach to the prevention and treatment of cardiovascular diseases.
Thymus medulla fosters generation of natural Treg cells, invariant γδ T cells, and invariant NKT cells: what we learn from intrathymic migration.
Cowan Jennifer E,Jenkinson William E,Anderson Graham
European journal of immunology
The organization of the thymus into distinct cortical and medullary regions enables it to control the step-wise migration and development of immature T-cell precursors. Such a process provides access to specialized cortical and medullary thymic epithelial cells at defined stages of maturation, ensuring the generation of self-tolerant and MHC-restricted conventional CD4(+) and CD8(+) αβ T cells. The migratory cues and stromal cell requirements that regulate the development of conventional αβ T cells have been well studied. However, the thymus also fosters the generation of several immunoregulatory T-cell populations that form key components of both innate and adaptive immune responses. These include Foxp3(+) natural regulatory T cells, invariant γδ T cells, and CD1d-restricted invariant natural killer T cells (iNKT cells). While less is known about the intrathymic requirements of these nonconventional T cells, recent studies have highlighted the importance of the thymus medulla in their development. Here, we review recent findings on the mechanisms controlling the intrathymic migration of distinct T-cell subsets, and relate this to knowledge of the microenvironmental requirements of these cells.
Molecular mechanisms underlying Th1-like Treg generation and function.
Kitz Alexandra,Dominguez-Villar Margarita
Cellular and molecular life sciences : CMLS
Since their 're-discovery' more than two decades ago, FOXP3 regulatory T cells (Tregs) have been an important subject of investigation in the biomedical field and our understanding of the mechanisms that drive their phenotype and function in health and disease has advanced tremendously. During the past few years it has become clear that Tregs are not a terminally differentiated population but show some degree of plasticity, and can, under specific environmental conditions, acquire the phenotype of effector T cells. In particular, recent works have highlighted the acquisition of a Th1-like phenotype by Tregs in several pathological environments. In this review we give an update on the concept of Treg plasticity and the advances in defining the molecular mechanisms that underlie the generation of Th1-like Tregs during an immune response and in different disease settings.
Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders.
Fasching Patrizia,Stradner Martin,Graninger Winfried,Dejaco Christian,Fessler Johannes
Molecules (Basel, Switzerland)
A disruption of the crucial balance between regulatory T-cells (Tregs) and Th17-cells was recently implicated in various autoimmune disorders. Tregs are responsible for the maintenance of self-tolerance, thus inhibiting autoimmunity, whereas pro-inflammatory Th17-cells contribute to the induction and propagation of inflammation. Distortion of the Th17/Treg balance favoring the pro-inflammatory Th17 side is hence suspected to contribute to exacerbation of autoimmune disorders. This review aims to summarize recent data and advances in targeted therapeutic modification of the Th17/Treg-balance, as well as information on the efficacy of candidate therapeutics with respect to the treatment of autoimmune diseases.
New insights into the mechanisms of Treg function.
Rothstein David M,Camirand Geoffrey
Current opinion in organ transplantation
PURPOSE OF REVIEW:CD4Foxp3 regulatory T cells (Tregs) are crucial in controlling immunity and self-tolerance. Consequently, in transplantation, Tregs play a central role in inhibiting acute rejection and promoting allograft tolerance. A more complete understanding of Treg biology may lead to novel therapeutic approaches to enhance Treg numbers and function. RECENT FINDINGS:The maintenance of self-tolerance in nonlymphoid tissues requires the differentiation of Tregs in secondary lymphoid organs from naïve-like central Tregs into effector Tregs. Antigen and environmental cues guide this Treg differentiation, which parallels the types of adaptive immune responses taking place, allowing them to enter and function within specific nonlymphoid tissues. In addition to controlling inflammation, tissue-infiltrating Tregs unexpectedly regulate nonimmune processes, including metabolic homeostasis and tissue repair. Finally, Tregs can be directly and specifically targeted in vivo to augment their numbers or enhance their function in both secondary lymphoid organs and nonlymphoid tissues. SUMMARY:Tregs exhibit a previously unrecognized breadth of function, which includes tissue-specific specialization and the regulation of both immune and nonimmune processes. This is of particular importance in transplantation since allo-reactive memory T cells can act directly within the allograft. Thus, therapeutic approaches may need to promote Treg function in transplanted tissue, as well as in secondary lymphoid organs. Such therapy would not only prevent inflammation and acute rejection, but may also promote nonimmune processes within the allograft such as tissue homeostasis and repair.
TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases.
Bystrom Jonas,Clanchy F I,Taher Taher E,Mangat Pam,Jawad Ali S,Williams Richard O,Mageed Rizgar A
TNFα is a principal pro-inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNFα inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNFα causes its effects by binding to either or both of two membrane-bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNFα and depending on whether the cytokine is membrane-bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNFα and T cell signalling proteins can significantly impact the outcome of TNFα receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNFα. However, recent evidence indicates that the relationship between TNFα and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNFα on different T cell subsets. This review will summarise knowledge on how TNFα modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNFα inhibitors.
Genetic and epigenetic basis of Treg cell development and function: from a FoxP3-centered view to an epigenome-defined view of natural Treg cells.
Morikawa Hiromasa,Sakaguchi Shimon
Naturally occurring regulatory T (nTreg) cells, which specifically express the transcription factor Forkhead box protein P3 (FoxP3), are indispensable for the maintenance of immunological self-tolerance and homeostasis. Recent studies have shown that developing nTreg cells in the thymus acquire a Treg-specific and stable hypomethylation pattern in a limited number of genes, which encode key molecules including FoxP3, essential for Treg cell function. This epigenetic change is acquired via T-cell receptor (TCR) stimulation, beginning prior to FoxP3 expression. The Treg-specific DNA hypomethylated regions generally act as gene enhancers in steady state nTreg cells, contributing to the stable expression of Treg function-associated key genes including Ctla4, Il2ra, and Ikzf4 in addition to Foxp3. Upon TCR stimulation of mature nTreg cells, FoxP3 strongly represses many genes including Il2, contributing to Treg suppressive activity. Thus, the Treg-specific epigenome alteration can determine the heritable Treg-specific gene network including Foxp3 regulation. Considering physiological presence of non-suppressive FoxP3(+) T cells in the immune system and loss of FoxP3 in Treg cells under certain immunological conditions, functional nTreg cells can be more accurately defined as a T-cell subpopulation possessing the Treg-type epigenome, rather than FoxP3(+) T cells. This epigenome-based definition of Treg cells would enable better understanding of functional stability, plasticity, and heterogeneity of Treg cells.
The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome.
Omenetti Sara,Pizarro Theresa T
Frontiers in immunology
T-helper 17 (Th17) and T-regulatory (Treg) cells are frequently found at barrier surfaces, particularly within the intestinal mucosa, where they function to protect the host from pathogenic microorganisms and to restrain excessive effector T-cell responses, respectively. Despite their differing functional properties, Th17 cells and Tregs share similar developmental requirements. In fact, the fate of antigen-naïve T-cells to either Th17 or Treg lineages is finely regulated by key mediators, including TGFβ, IL-6, and all-trans retinoic acid. Importantly, the intestinal microbiome also provides immunostimulatory signals, which can activate innate and downstream adaptive immune responses. Specific components of the gut microbiome have been implicated in the production of proinflammatory cytokines by innate immune cells, such as IL-6, IL-23, IL-1β, and the subsequent generation and expansion of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of intestinal Tregs that can actively induce mucosal tolerance. As such, dysbiosis of the gut microbiome may not solely represent a consequence of gut inflammation, but rather shape the Treg/Th17 commitment and influence susceptibility to inflammatory bowel disease. In this review, we discuss Treg and Th17 cell plasticity, its dynamic regulation by the microbiome, and highlight its impact on intestinal homeostasis and disease.
TREG-cell therapies for autoimmune rheumatic diseases.
Miyara Makoto,Ito Yoshinaga,Sakaguchi Shimon
Nature reviews. Rheumatology
Naturally occurring Foxp3(+)CD25(+)CD4(+) regulatory T (TREG) cells maintain immunological self-tolerance and prevent a variety of autoimmune diseases, including rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. In animal models of rheumatic disease, autoimmune responses can be controlled by re-establishing the T-cell balance in favour of TREG cells. Here we discuss three potential strategies for the clinical use of TREG cells to treat autoimmune rheumatic disease: expansion of self-antigen-specific natural TREG cells in vivo; propagation of antigen-specific natural TREG cells ex vivo, by in vitro antigenic stimulation, and subsequent transfer back into the host; or conversion of antigen-specific conventional T cells into TREG cells in vivo or ex vivo. These strategies require depletion of the effector T cells that mediate autoimmunity before initiating TREG-cell-based therapies. Immunotherapies that target TREG cells, and the balance of TREG cells and autoreactive T cells, are therefore an important modality for the treatment of autoimmune rheumatic disease.
The Functional Stability of FOXP3 and RORγt in Treg and Th17 and Their Therapeutic Applications.
Ren J,Li B
Advances in protein chemistry and structural biology
The balance of CD4CD25FOXP3 regulatory T cells (Tregs) and effector T cells plays a key role in maintaining immune homeostasis, while the imbalance of them is related to many inflammatory diseases in both human and mice. Here we discuss about the plasticity of Tregs and Th17 cells, and the related human diseases resulted from the imbalance of them. Further, we will focus on the mechanisms regulating the plasticity between Tregs and Th17 cells and the potential therapeutic strategies by targeting regulators of the expression and activity of FOXP3 and RORγt or regulators of Treg/Th17 balance in autoimmune diseases, allergy, infection, and cancer.
Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases.
Abdel-Gadir Azza,Massoud Amir H,Chatila Talal A
Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.
Treg functional stability and its responsiveness to the microenvironment.
Barbi Joseph,Pardoll Drew,Pan Fan
Regulatory T cells (Tregs) prevent autoimmunity and tissue damage resulting from excessive or unnecessary immune activation through their suppressive function. While their importance for proper immune control is undeniable, the stability of the Treg lineage has recently become a controversial topic. Many reports have shown dramatic loss of the signature Treg transcription factor Forkhead box protein 3 (Foxp3) and Treg function under various inflammatory conditions. Other recent studies demonstrate that most Tregs are extremely resilient in their expression of Foxp3 and the retention of suppressive function. While this debate is unlikely to be settled in the immediate future, improved understanding of the considerable heterogeneity within the Foxp3(+) Treg population and how Treg subsets respond to ranging environmental cues may be keys to reconciliation. In this review, we discuss the diverse mechanisms responsible for the observed stability or instability of Foxp3(+) Treg identity and function. These include transcriptional and epigenetic programs, transcript targeting, and posttranslational modifications that appear responsive to numerous elements of the microenvironment. These mechanisms for Treg functional modulation add to the discussion of Treg stability.
Advances on CD8+ Treg Cells and Their Potential in Transplantation.
Bézie Séverine,Anegon Ignacio,Guillonneau Carole
Although cluster of differentiation (CD)8 regulatory T (Treg) cells have been in the last 20 years more studied since evidences of their role in tolerance as been demonstrated in transplantation, autoimmune diseases and cancer, their characteristics are still controversial. In this review, we will focus on recent advances on CD8 Treg cells and description of a role for CD8 Treg cells in tolerance in both solid organ transplantation and graft-versus-host disease and their potential for clinical trials.
Molecular Mechanisms of the Action of Vitamin A in Th17/Treg Axis in Multiple Sclerosis.
Abdolahi Mina,Yavari Parvaneh,Honarvar Niyaz Mohammadzadeh,Bitarafan Sama,Mahmoudi Maryam,Saboor-Yaraghi Ali Akbar
Journal of molecular neuroscience : MN
Multiple sclerosis (MS) is an autoinflammatory disease of the central nervous system (CNS). The immunopathogenesis of this disease involves an impaired balance of T helper (Th) 17 cells and regulatory T (Tregs) cells. MS is an autoinflammatory disease characterized by the degeneration of the CNS. For many years, MS has been considered to be an autoreactive Th1 and Th17 cell-dominated disease. The activity and number of Th17 cells are increased in MS; however, the function and number of Treg cells are reduced. Therefore, in MS, the balance between Th17 cells and Treg cells is impaired. Th17 cells produce pro-inflammatory cytokines, which play a role in experimental autoimmune encephalomyelitis (EAE) and MS. However, Treg cell-mediated production of cytokines maintains immune homeostasis and can ameliorate the progression of MS. These observations, therefore, confirm the pathogenic and protective role of Th17 and Treg cells, respectively, and highlight the importance of maintaining the balance of both of these cell types. Evidence suggests that vitamin A and its active metabolites (all-trans-retinoic acid and 9-cis-retinoic acid) modulate the imbalance of Th17 and Treg cells through multiple molecular pathways and can be considered as a promising target in the prevention and treatment of MS.
The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part I: Treg properties and functions.
Nedoszytko Bogusław,Lange Magdalena,Sokołowska-Wojdyło Małgorzata,Renke Joanna,Trzonkowski Piotr,Sobjanek Michał,Szczerkowska-Dobosz Aneta,Niedoszytko Marek,Górska Aleksandra,Romantowski Jan,Skokowski Jarosław,Kalinowski Leszek,Nowicki Roman
Postepy dermatologii i alergologii
Regulatory T cells (Treg) can be divided into two types: the natural cells (tTreg), which arise in the thymus, and the induced cells (iTreg), which are produced in peripheral tissues during immune response. The most recently published studies indicate that the supervisory functions of these cells are weakened in the pathogenesis of autoimmune and neoplastic diseases of the skin. This may be a result of the domination of other immune cells in the skin, such as Th1/Th17/Th22 and Tc1 type in psoriasis and Th2 in atopic dermatitis. The excessive activity of Treg cells can lead to immunosuppression and decrease in the number of Th1 cells, which promote the development and progression of skin cancers. In the case of cutaneous T-cell lymphomas, there are suggestions that tumor progression is associated with the acquisition of the suppressor phenotype of malignant cells. There is genetic background of Treg dysfunction in skin disorders. This article describes the types and functions of Treg cells.
Treg-Centric View of Immunosuppressive Drugs in Transplantation: A Balancing Act.
Camirand G,Riella L V
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Regulatory CD4+ Foxp3+ T cells (Tregs) are critical in controlling immunity and tolerance. Thus, preserving Treg numbers and function in transplanted patients is essential for the successful minimization of maintenance immunosuppression. Multiple cellular signals control the development, differentiation, and function of Tregs. Many of these signals are shared with conventional Foxp3 T cells (Tconv) and are targeted by immunosuppressive drugs, negatively affecting both Tregs and Tconv. Because intracellular signals vary in optimal intensity in different T cell subsets, improved specificity in immunosuppressive regimens must occur to benefit long-term transplant outcomes. In this regard, recent advances are gradually uncovering differences in the signals required in Tregs and Tconv biology, opening the door to new potential therapeutic approaches to either enhance or spare Tregs. In this review, we will explain the prominent cell signaling pathways critical for Treg maintenance and function, while reporting the effects of immunosuppressive drugs targeting these signaling pathways in clinical transplantation settings.
Ubiquitin-dependent regulation of Foxp3 and Treg function.
Barbi Joseph,Pardoll Drew M,Pan Fan
Regulatory T (Treg) cells are crucial enforcers of immune homeostasis. Their characteristic suppressive function largely arises from an equally unique pattern of gene expression. A complex network of factors and processes contribute to this 'signature' Treg gene expression landscape. Many of these alter the level and activity of the Treg-defining transcription factor Foxp3. As stable expression of Foxp3 is important for the ability of Treg cells to successfully prevent excessive or inappropriate immune activation, uncovering the mechanisms regulating Foxp3 level is required for the understanding and therapeutic exploitation of Tregs. While transcriptional regulation of the Foxp3 gene has been studied in depth, additional regulatory layers exist controlling the expression and activity of this key transcription factor. These include less-defined mechanisms active at the post-translational level. These pathways are just beginning to be elucidated. Here, we summarize emerging evidence for distinct, post-translationally active, ubiquitin-dependent pathways capable of controlling the activation and expression of Foxp3 and the function of Tregs. These pathways offer untapped opportunities for therapeutic fine-tuning of Tregs and their all-important restraint of the immune system.
Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression.
Gianchecchi Elena,Fierabracci Alessandra
Frontiers in immunology
Regulatory T (Treg) cells represent a subpopulation of suppressor CD4 T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity.
Treg Cell Differentiation: From Thymus to Peripheral Tissue.
Richards David M,Delacher Michael,Goldfarb Yael,Kägebein Danny,Hofer Ann-Cathrin,Abramson Jakub,Feuerer Markus
Progress in molecular biology and translational science
Regulatory T cells (Tregs) are crucial mediators of self-tolerance in the periphery. They differentiate in the thymus, where interactions with thymus-resident antigen-presenting cells, an instructive cytokine milieu, and stimulation of the T cell receptor lead to the selection into the Treg lineage and the induction of Foxp3 gene expression. Once mature, Treg cells leave the thymus and migrate into either the secondary lymphoid tissues, e.g., lymph nodes and spleen, or peripheral nonlymphoid tissues. There is growing evidence that Treg cells go beyond the classical modulation of immune responses and also play important functional roles in nonlymphoid peripheral tissues. In this review, we summarize recent findings about the thymic Treg lineage differentiation as well as the further specialization of Treg cells in the secondary lymphoid and in the peripheral nonlymphoid organs.
The Balance of Th17 versus Treg Cells in Autoimmunity.
Lee Gap Ryol
International journal of molecular sciences
T helper type 17 (Th17) cells and pTreg cells, which share a common precursor cell (the naïve CD4 T cell), require a common tumor growth factor (TGF)-β signal for initial differentiation. However, terminally differentiated cells fulfill opposite functions: Th17 cells cause autoimmunity and inflammation, whereas Treg cells inhibit these phenomena and maintain immune homeostasis. Thus, unraveling the mechanisms that affect the Th17/Treg cell balance is critical if we are to better understand autoimmunity and tolerance. Recent studies have identified many factors that influence this balance; these factors range from signaling pathways triggered by T cell receptors, costimulatory receptors, and cytokines, to various metabolic pathways and the intestinal microbiota. This review article summarizes recent advances in our understanding of the Th17/Treg balance and its implications with respect to autoimmune disease.
[Immunomodulatory effects of Treg and Th17 cells in parasitic infections and hygiene hypothesis].
Ying-Ying Yang,Jun-Qi Yang
Zhongguo xue xi chong bing fang zhi za zhi = Chinese journal of schistosomiasis control
The parasitic infection is still a severe public health problem in developing countries, which threatens people's health and social development. With the advances of molecular biology and immunology, more and more insights have been reached on the immunity and immunopathogenesis to parasitic infections. CD4 T cells play a central role in the host's immunosurveillance and immunoregulation. Traditionally, naive CD4 T cells are considered to be able to differentiate into Th1 and Th2 cell subsets both and . These Th1 and Th2 cells secret diverse cytokine profiles to exert different functions. Later, two new subsets of CD4 T cells, Th17 and Treg cells, have been discovered. They are completely different from traditional Th1 and Th2 cells with independent differentiation and regulation mechanism. Ample studies suggest that Treg and Th17 cells play a key role in a variety of parasitic diseases. Furthermore, Treg and Th17 cells have been got increasing attention for their involvement in the hygiene hypothesis. Based on the current advances of researches of Treg and Th17 cells, we make a brief review about immunomodulatory effects of these two subsets in parasitic infections as well as the hygiene hypothesis.
Th17 and Treg lymphocytes in obesity and Type 2 diabetic patients.
Wang Mei,Chen Fuqiong,Wang Jingli,Zeng Zhixuan,Yang Qin,Shao Shiying
Clinical immunology (Orlando, Fla.)
Assumption that the pathogenesis of obesity-associated type 2 diabetes (T2DM) encompasses inflammation and autoimmune aspects is increasingly recognized. In the state of obesity and T2DM, the imbalance of T helper 17 (Th17) cells and regulatory T (Treg) cells are observed. These alterations reflect a loss of T cell homeostasis, which may contribute to tissue and systemic inflammation and immunity in T2DM. In this review we will discuss the accumulating data supporting the concept that Th17/Treg mediated immune responses are present in obesity-related T2DM pathogenesis, and provide evidences that restoration of Th17/Treg imbalance may be a possible therapeutic avenue for the prevention and treatment of T2DM and its complications.
T regulatory (Treg) and T helper 17 (Th17) lymphocytes in thyroid autoimmunity.
González-Amaro Roberto,Marazuela Mónica
Different immune cell subsets have a relevant role in the pathogenesis of and tissue damage seen in autoimmune thyroid diseases (AITD), including T regulatory (Treg) lymphocytes and T helper (Th) 17 cells. There are several types of CD4+ Treg cells (Foxp3+, CD69+, Tr1), which are able to prevent the appearance of autoimmune diseases, down regulating the immune response and the inflammatory phenomenon. However, despite their presence in peripheral blood and thyroid tissue from patients with AITD, these cells are apparently unable to put down the autoimmune process. Moreover, many reports indicate the involvement of Th17 cells in chronic inflammatory diseases, including AITD. Nevertheless, it is now evident that these lymphocytes show a remarkable plasticity, giving rise to anti-inflammatory (including Treg lymphocytes) and pro-inflammatory cell subtypes. Nowadays, both Treg and Th17 cells must be considered as key elements in the pathogenesis of AITD as well as plausible potential targets for the next generation of therapeutic options of this condition.
FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases.
Nie Jia,Li Yang Yang,Zheng Song Guo,Tsun Andy,Li Bin
Frontiers in immunology
CD4(+)CD25(+) regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS). In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals. Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender. Here, we review recent findings on the regulation of FOXP3 activity in Treg cells and also discuss gender difference in the determination of Treg cell function in autoimmune diseases.
Dual effect of T helper cell 17 (Th17) and regulatory T cell (Treg) in liver pathological process: From occurrence to end stage of disease.
Zhang Haoran,Jiang Zhenzhou,Zhang Luyong
Liver disease is a complicated pathological status with acute or chronic progressions, causing a series of damages to liver and massive burden to public health and society. Th17 and Treg, two subsets of CD4 T helper cells, seem to keep a subtle balance in the maintenance of organic immune homeostasis including liver. The dysfunction of Th17/Treg balance in liver has been proved associated with hepatic injury and disease. Herein, we summarized the research advance of Th17 and Treg cells in different phenotypes of liver diseases in the past decade. It is known to all that hepatic diseases start from stimulations or infections like virus, autoimmune, alcohol and so on in the early stage, which would cause inflammation. With the disease consistently existed, severe outcomes like cirrhosis and hepatocellular carcinoma appear finally. In conclusion, it is found that Th17 and Treg cells serve as an important role in the immune response imbalance of liver diseases from the beginning to the end stage. However, the effect of these two subsets of CD4 T helper cells is not a stereotype. Pathological role which exacerbates the disease and protective character which inhibits damage to liver are co-existed in the effect of Th17 and Treg cells. Still, more studies should be carried out to enrich the understandings of liver disease and Th17/Treg immune balance in the future.
Mechanisms of human FoxP3 T cell development and function in health and disease.
Attias M,Al-Aubodah T,Piccirillo C A
Clinical and experimental immunology
Regulatory T (T ) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage-defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that T cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non-suppressive T cells exist in human blood that are otherwise indistinguishable from one another using classical T cell markers such as CD25 and FoxP3. Moreover, murine T cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (T ) cells. However, this plasticity can also result in T cell lineage instability and acquisition of proinflammatory T cell functions. Consequently, these dysfunctional CD4 FoxP3 T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human T cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to T cell antigen-specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3 T cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human T cells, and how abrogating these mechanisms can lead to lineage instability and T cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer.
Treg and Th17 cells in inflammatory periapical disease: a systematic review.
Naufel André Oliveira,Aguiar Maria Cássia Ferreira,Madeira Fernandes Moreira,Abreu Lucas Guimarães
Brazilian oral research
The process involved in periapical lesions, which occur as an outcome of pulpal necrosis, is regulated by the immune system including regulatory T cells (Treg) and T helper 17 cell (Th17) responses. The objective of this study was to conduct a frequency systematic review to determine the presence of Treg/Th17 responses and the influence of these cells in the progression of chronic inflammatory periapical lesions in humans. A systematic computerized search was carried out in Pubmed, Medline, Web of Science and Scopus electronic databases from their date of inception through the first week of May 2017. In addition, the reference lists of the included articles and the grey literature were hand-searched. Articles that evaluated the presence and influence of Treg/Th17 in the progression of human periapical lesions were included. Study selection and the quality assessment of the included articles (using the Newcastle-Ottawa scale) were carried out by two authors. Fifty-seven titles/abstracts were screened and eight studies met the eligibility criteria and were included in this systematic review. The included studies showed large variation in the type of periapical lesion assessed, mean age, age range, type of experiment and findings regarding the participation of Th17 and Treg in the status of inflammatory periapical lesions. The studies showed the involvement of Treg in the modulation of the inflammatory response in radicular cysts and periapical granulomas. This systematic review highlights the relationship between Treg and Th17 acting in a subtle balance inhibiting or promoting the progression of human periapical lesions.
tTregs, pTregs, and iTregs: similarities and differences.
Shevach Ethan M,Thornton Angela M
Foxp3(+) T-regulatory cells (Tregs) are primarily generated in the thymus (tTreg), but also may be generated extrathymically at peripheral sites (pTreg), or induced in cell culture (iTreg) in the presence of transforming growth factor β (TGFβ). A major unresolved issue is how these different populations of Tregs exert their suppressive function in vivo. We have developed novel systems in which the function of Tregs can be evaluated in vivo in normal mice. Our studies demonstrate that one prominent mechanism of action of polyclonal tTregs is to inhibit T-effector cell trafficking to the target organ, while antigen-specific iTregs primarily prevent T-cell priming by acting on antigen-presenting dendritic cells (DCs). Interleukin-10 (IL-10) plays an important role in the suppressive function of antigen-specific iTregs by controlling the expression of MARCH1 and CD83 on the DC. Activated tTregs may mediate infectious tolerance by delivery of cell surface-expressed TGFβ to naive responder T cells to generate pTregs. Manipulation of Treg function will require the ability to differentiate tTregs from pTregs and iTregs. The expression of the transcription factor Helios has proven to be a useful marker for the identification of stable tTregs in both mouse and human.