CD4+ CD25+ regulatory T cells (Tregs) expressing the lineage-specific marker Foxp3 represent an important regulatory T cell that is essential for maintaining peripheral tolerance. Although it was believed that Treg development is solely dependent on the thymus, accumulating evidence demonstrates that Tregs can also be induced in the periphery. Considering the various origins of peripherally developed CD4+ CD25+ Foxp3+ regulatory T cells, it seems likely that multiple factors are involved in the peripheral generation of Tregs.
Peripheral Tolerance ; T-Lymphocytes, Regulatory* ; Thymus Gland

The immune system is continuously exposed to great amounts of different antigens from both food and intestinal microbes. Immune tolerance to these antigens is very important for intestinal and systemic immune homeostasis. Oral tolerance is a specific type of peripheral tolerance induced by exposure to antigen via the oral route. Investigations on the role of intestinal immune system in preventing hypersensitivity reactions to innocuous dietary and microbial antigens have been intensively performed during the last 2 decades. In this review article, we discuss how food allergens are recognized by the intestinal immune system and draw attention to the role of regulatory T (Treg) and B (Breg) cells in the establishment of oral tolerance and tolerogenic features of intestinal dendritic cells. We also emphasize the potential role of tonsils in oral tolerance induction because of their anatomical location, cellular composition, and possible usage to develop novel ways of specific immunotherapy for the treatment of allergic diseases.
Allergens ; Dendritic Cells ; Food Hypersensitivity ; Homeostasis ; Hypersensitivity ; Immune System ; Immune Tolerance ; Immunotherapy ; Palatine Tonsil ; Peripheral Tolerance

Regulatory T (TReg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumor immunity. TReg cells characterized by expression of the transcription factor Foxp3 play a key role in immune homeostasis. Rather than a monomorphic population strictly determined by Foxp3 as a 'master regulator', the emerging view is one of TReg cells as a population with many levels of complexity. Distinct subphenotypes of Foxp3+ TReg cells are found in different anatomical locations. This review will focus on these novel aspects of TReg cell diversity, and discuss recent findings regarding human TReg cells, including the ontogeny and development of TReg cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by TReg cell subsets and factors that regulate TReg cell lineage commitment. We also will discuss future studies that are needed for the successful therapeutic use of human TReg cells.
Autoimmune Diseases ; Homeostasis ; Humans ; Immune System ; Memory ; Peripheral Tolerance ; Phenotype ; T-Lymphocytes, Regulatory ; Transcription Factors

Self/non-self discrimination and unresponsiveness to self is the fundamental properties of the immune system. Self-tolerance is a state in which the individual is incapable of developing an immune response to an individual's own antigens and it underlies the ability to remain tolerant of individual's own tissue components. Several mechanisms have been postulated to explain the tolerant state. They can be broadly classified into two groups: central tolerance and peripheral tolerance. Several mechanisms exist, some of which are shared between T cells and B cells. In central tolerance, the recognition of self-antigen by lymphocytes in bone marrow or thymus during development is required, resulting in receptor editing (revision), clonal deletion, anergy or generation of regulatory T cells. Not all self-reactive B or T cells are centrally purged from the repertoire. Additional mechanisms of peripheral tolerance are required, such as anergy, suppression, deletion or clonal ignorance. Tolerance is antigen specific. Generating and maintaining the self-tolerance for T cells and B cells are complex. Failure of self-tolerance results in immune responses against self-antigens. Such reactions are called autoimmunity and may give rise to autoimmune diseases. Development of autoimmune disease is affected by properties of the genes of the individual and the environment, both infectious and non-infectious. The host's genes affect its susceptibility to autoimmunity and the environmental factors promote the activation of self-reactive lymphocytes, developing the autoimmunity. The changes in participating antigens (epitope spreading), cells, cytokines or other inflammatory mediators contribute to the progress from initial activation to a chronic state of autoimmune diseases.
Autoantigens ; Autoimmune Diseases ; Autoimmunity* ; B-Lymphocytes ; Bone Marrow ; Central Tolerance ; Clonal Deletion ; Cytokines ; Discrimination (Psychology) ; Immune System ; Lymphocytes ; Peripheral Tolerance ; T-Lymphocytes ; T-Lymphocytes, Regulatory ; Thymus Gland

The lymphatic vasculature has been regarded as a passive conduit for interstitial fluid and responsible for the absorption of macromolecules such as proteins or lipids and transport of nutrients from food. However, emerging data show that the lymphatic vasculature system plays an important role in immune modulation. One of its major roles is to coordinate antigen transport and immune-cell trafficking from peripheral tissues to secondary lymphoid organs, lymph nodes. This perspective was recently updated with the notion that the interaction between lymphatic endothelial cells and leukocytes controls the immune-cell migration and immune responses by regulating lymphatic flow and various secreted molecules such as chemokines and cytokines. In this review, we introduce the lymphatic vasculature networks and genetic transgenic models for research on the lymphatic vasculature system. Next, we discuss the contribution of lymphatic endothelial cells to the control of immune-cell trafficking and to maintenance of peripheral tolerance. Finally, the physiological roles and features of the lymphatic vasculature system are further discussed regarding inflammation-induced lymphangiogenesis in a pathological condition, especially in mucosal tissues such as the gastrointestinal tract and respiratory tract.
Absorption ; Chemokines ; Cytokines ; Endothelial Cells ; Endothelium ; Extracellular Fluid ; Gastrointestinal Tract ; Leukocytes ; Lymph Nodes ; Lymphangiogenesis ; Mucous Membrane ; Peripheral Tolerance ; Respiratory System

Systemic lupus erythematosus (lupus) is an autoimmune disease that affects primarily women, especially those of reproductive age. Lupus is a prototypic organ non-specific autoimmune disease that may affect any organ in the body resulting in displaying a broad spectrum of clinical and immunological manifestations. The pathogenesis of lupus involves a complex interplay between genetic and environmental factors and the adaptive and innate immune systems. Defects in central and peripheral tolerance, increased antigenic load, excess T-cell help, B cell hyperactivity, autoantibody production and cytokine imbalance, ultimately lead to immune-complex formation and complement activation causing immunologically mediated organ damage, culminating in premature death. There is an urgent need for the development of novel agents since many patients are refractory to traditional agents. However, there are two hurdles that make development of new therapeutic agents difficult. First, we do not understand the whole picture of the pathogenesis of lupus because of its complex and multi-systemic presentation. Secondly, lupus lacks a reliable and sensitive biomarker for measuring disease activity, and a standardized method for defining response to therapy. Nevertheless, great advances have been made during the past 10 years because of the great efforts of basic researchers and clinicians on elucidating the cause of the disease, and participation of pharmaceutical and biotechnical companies in the development of novel agents. My goal was to evaluate the efficacy and safety of novel pharmaceutical agents by a comprehensive review of open-label and randomized clinical trials conducted in patients with lupus.
Autoimmune Diseases ; Biological Agents ; Complement Activation ; Female ; Humans ; Immune System ; Lupus Erythematosus, Systemic ; Mortality, Premature ; Peripheral Tolerance ; Pharmaceutical Services ; T-Lymphocytes

Developments in our comprehension of the autoimmune and inflammation mechanisms in rheumatoid arthritis (RA) have produced targeted therapies that block aberrant immune cells and cytokine networks, and improved treatment of RA patients considerably. Nevertheless, limitations of these treatments include incomplete treatment response, adverse effects requiring drug withdrawal, and refractory cases. Hence, many researchers have redirected efforts towards investigation of other biological aspects of RA, including the mechanisms driving joint tissue repair and balanced immune regulation. This investigation focuses on mesenchymal stem cell (MSC) research, with the ultimate goal of developing interventions for immune modulation and repair of damaged joints. MSCs are multipotent cells capable of differentiating into mesodermal lineage cells. These cells have also attracted interest for their anti-inflammatory and immunomodulatory capacities. They have many distinctive immunological properties, inhibiting the proliferation and production of cytokines by T, B, natural killer, and dendritic cells. Indeed, MSCs have the capacity to regulate immunity-induced peripheral tolerance, suggesting they can be used as therapeutic tools in RA. This review discusses properties of MSCs, in vitro studies, animal studies, and clinical trials involving MSCs. Our review discusses the current knowledge of the mechanisms of MSC-mediated immunosuppression and potential therapeutic uses of MSCs in RA.
Animals ; Arthritis, Rheumatoid* ; Comprehension ; Cytokines ; Dendritic Cells ; Humans ; Immunosuppression ; In Vitro Techniques ; Inflammation ; Joints ; Mesenchymal Stromal Cells* ; Mesoderm ; Peripheral Tolerance ; Therapeutic Uses

The discovery of microRNA (miRNA) is one of the major scientific breakthroughs in recent years and has revolutionized current cell biology and medical science. miRNAs are small (19~25nt) noncoding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region (3'UTR) of specific messenger RNAs (mRNAs) for degradation of translation repression. Genetic ablation of the miRNA machinery, as well as loss or degradation of certain individual miRNAs, severely compromises immune development and response, and can lead to immune disorders. Several sophisticated regulatory mechanisms are used to maintain immune homeostasis. Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. Recent publications have provided compelling evidence that miRNAs are highly expressed in Treg cells, that the expression of Foxp3 is controlled by miRNAs and that a range of miRNAs are involved in the regulation of immunity. A large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, cardiovascular disease and diabetes, as well as psychiatric and neurological diseases. Although it is still unclear how miRNA controls Treg cell development and function, recent studies certainly indicate that this topic will be the subject of further research. The specific circulating miRNA species may also be useful for the diagnosis, classification, prognosis of diseases and prediction of the therapeutic response. An explosive literature has focussed on the role of miRNA. In this review, I briefly summarize the current studies about the role of miRNAs in Treg cells and in the regulation of the innate and adaptive immune response. I also review the explosive current studies about clinical application of miRNA.
3' Untranslated Regions ; Adaptive Immunity ; Autoimmune Diseases ; Cardiovascular Diseases ; Gene Expression ; Homeostasis ; Immune System Diseases ; MicroRNAs ; Peripheral Tolerance ; Prognosis ; Repression, Psychology ; RNA, Messenger ; RNA, Untranslated ; T-Lymphocytes, Regulatory

CD4⁺ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead to the development of autoimmune diseases, such as type-1 diabetes (T1D). T1D is a T cell-mediated autoimmune disease characterized by islet β cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. Tregs play a critical role in the development of T1D and participate in peripheral tolerance. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat T1D as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) remain undefined, especially molecular mechanisms that direct differentiation of such Tregs. Auto Ag-specific PSC-Tregs can be programmed to be tissue-associated and infiltrate to local inflamed tissue (e.g., islets) to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. Developing auto Ag-specific PSC-Tregs can reduce overall immunosuppression after adoptive transfer by accumulating inflamed islets, which drives forward the use of therapeutic PSC-Tregs for cell-based therapies in T1D.
Adoptive Transfer ; Autoimmune Diseases ; Autoimmunity ; Glucose ; Homeostasis ; Immunosuppression ; Immunotherapy* ; Peripheral Tolerance ; Pluripotent Stem Cells ; Stem Cells ; T-Lymphocytes ; T-Lymphocytes, Regulatory*

CD4⁺ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead to the development of autoimmune diseases, such as type-1 diabetes (T1D). T1D is a T cell-mediated autoimmune disease characterized by islet β cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. Tregs play a critical role in the development of T1D and participate in peripheral tolerance. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat T1D as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) remain undefined, especially molecular mechanisms that direct differentiation of such Tregs. Auto Ag-specific PSC-Tregs can be programmed to be tissue-associated and infiltrate to local inflamed tissue (e.g., islets) to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. Developing auto Ag-specific PSC-Tregs can reduce overall immunosuppression after adoptive transfer by accumulating inflamed islets, which drives forward the use of therapeutic PSC-Tregs for cell-based therapies in T1D.
Adoptive Transfer ; Autoimmune Diseases ; Autoimmunity ; Glucose ; Homeostasis ; Immunosuppression ; Immunotherapy* ; Peripheral Tolerance ; Pluripotent Stem Cells ; Stem Cells ; T-Lymphocytes ; T-Lymphocytes, Regulatory*