Regulatory T cells in autoimmune diseases: anti-ergotypic T cells

T regulatory cells play an important role in regulating T-cell responses to self-antigens and control autoimmunity and autoimmune disease. Anti-ergotypic T cells are a subset of such regulatory T cells that respond to activation markers, ergotopes, expressed on other activated T cells. Anti-ergotypic T cells do not respond to nonactivated T cells. Ergotopes include the a-chain of the IL-2 receptor (CD25). Anti-ergotypic T cells were found to downregulate experimental diseases such as experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA). Anti-ergotypic T cells are present in humans and are activated after T-cell vaccination. Here we review anti-ergotypic T cells in animal models and in humans and contrast anti-ergotypic T cells with other regulatory T-cell subsets.     

Regulatory T cells in autoimmune neuroinflammation

Regulatory T cells are the central element for the maintenance of peripheral tolerance. Several subtypes of regulatory T (Treg) cells have been described, and most of them belong to the CD4⁺ T-helper (Th) cell lineage. These specific subtypes can be discriminated according to phenotype and function. Forkhead box protein 3 (FoxP3)-expressing natural Treg cells (Tregs) and IL-10-producing, T-regulatory type 1 cells (Tr1) are the best-studied types of CD4⁺ regulatory T cells in humans and experimental animal models. It was shown that they play a crucial role during autoimmune neuroinflammation. Both cells types seem to be particularly important for multiple sclerosis (MS). Here, we discuss the role of CD4⁺ regulatory T cells in autoimmune neuroinflammation with an emphasis on Tregs and Tr1 cells in MS.     

调节性B细胞与自身免疫性疾病

由于B细胞具有分泌抗体的能力,因此常被认为是免疫应答的正向促进因素,然而,研究发现,某些B细胞也能通过分泌调节性细胞因子(如IL-10、TGF-β等)来负向调节免疫过程,以及通过细胞间接触的方式直接作用于致病性T细胞.这种B细胞被定义为调节性B细胞(regulatory B cells,Bregs).许多学者已经阐释了Breg细胞在炎症和自身免疫疾病的动物模型中的调节作用.     

调节性B细胞与自身免疫性疾病

以往认为,B淋巴细胞在自身免疫病中作为致病性淋巴细胞发挥作用.近年却发现,在自身免疫病小鼠模型中,采用B细胞清除疗法会加重疾病进程,提示B细胞具有免疫调节功能.调节性B细胞(Breg)是新近发现的一群新的B细胞亚群,它存在于B细胞多个亚型中.Breg通过刺激其表面分子,诱导释放调节性细胞因子如IL-10发挥调节作用.在不同自身免疫性疾病中,各种免疫细胞都可以成为Breg作用的靶细胞,表明Breg在自身免疫病复杂网络中的强大调节作用.     

调节性B细胞与自身免疫性疾病

以往认为,B淋巴细胞在自身免疫病中作为致病性淋巴细胞发挥作用。近年却发现,在自身免疫病小鼠模型中,采用B细胞清除疗法会加重疾病进程,提示B细胞具有免疫调节功能。调节性B细胞（Breg）是新近发现的一群新的B细胞亚群,它存在于B细胞多个亚型中。Breg通过刺激其表面分子,诱导释放调节性细胞因子如IL-10发挥调节作用。在不同自身免疫性疾病中,各种免疫细胞都可以成为Breg作用的靶细胞,表明Breg在自身免疫病复杂网络中的强大调节作用。     

调节性B细胞与自身免疫性疾病

以往认为,B淋巴细胞在自身免疫病中作为致病性淋巴细胞发挥作用.近年却发现,在自身免疫病小鼠模型中,采用B细胞清除疗法会加重疾病进程,提示B细胞具有免疫调节功能.调节性B细胞(Breg)是新近发现的一群新的B细胞亚群,它存在于B细胞多个亚型中.Breg通过刺激其表面分子,诱导释放调节性细胞因子如IL-10发挥调节作用.在不同自身免疫性疾病中,各种免疫细胞都可以成为Breg作用的靶细胞,表明Breg在自身免疫病复杂网络中的强大调节作用.     

Regulatory T cells in experimental autoimmune disease

During the past 10 years, CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg) have been extensively studied for their function in autoimmune disease. This review summarizes the evidence for a role of Treg in suppression of innate and adaptive immune responses in experimental models of autoimmunity including arthritis, colitis, diabetes, autoimmune encephalomyelitis, lupus, gastritis, oophoritis, prostatitis, and thyroiditis. Antigen-specific activation of Treg, but antigen-independent suppressive function, emerges as a common paradigm derived from several disease models. Treg suppress conventional T cells (Tcon) by direct cell contact in vitro. However, downmodulation of dendritic cell function and secretion of inhibitory cytokines such as IL-10 and TGF-β might underlie Treg function in vivo. The final outcome of autoimmunity vs tolerance depends on the balance between stimulatory signals (Toll-like receptor engagement, costimulation, and antigen dose) and inhibitory signals from Treg. Whereas most experimental settings analyze the capacity of Treg to prevent onset of autoimmune disease, more recent efforts indicate successful treatment of ongoing disease. Thus, Treg are on the verge of moving from experimental animal models into clinical applications in humans.     

Regulatory T cells in spontaneous autoimmune encephalomyelitis

Summary: Spontaneous experimental autoimmune encephalomyelitis (EAE) develops in 100% of mice harboring a monoclonal myelin basic protein (MBP)-specific CD4⁺αβ T-cell repertoire. Monoclonality of the αβ T-cell repertoire can be achieved by crossing MBP-specific T-cell receptor (TCR) transgenic mice with either RAG^−/− mice or TCR α^−/−/TCR β^−/− double knockout mice. Spontaneous EAE can be prevented by a single administration of purified CD4⁺ splenocytes or thymocytes obtained from wild-type syngeneic mice. The regulatory T cells (T-reg) that protect from spontaneous EAE need not express the CD25 marker, as effective protection can be attained with populations depleted of CD25⁺ T cells. Although the specificity of the regulatory T cells is important for their generation or regulatory function, T cells that protect from spontaneous EAE can have a diverse TCR α and β chain composition. T-reg cells expand poorly in vivo , and appear to be long lived. Finally, precursors for T-reg are present in fetal liver as well as in the bone marrow of aging mice. We propose that protection of healthy individuals from autoimmune diseases involves several layers of regulation, which consist of CD4⁺CD25⁺ regulatory T cells, CD4⁺CD25⁻ T-reg cells, and anti-TCR T cells, with each layer potentially operating at different stages of T-helper cell-mediated immune responses.     

Regulatory T cells and autoimmune disease

Summary: Although T‐cell clones bearing T‐cell receptors with high affinity for self‐peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T‐cell repertoire remains strongly biased toward self‐peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4⁺CD25⁺ T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T‐effector cells as a target molecule for Treg‐dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T‐cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa‐1 on effector T cells is not addressed in this review.     

Regulatory T cells in primary immunodeficiency diseases

PURPOSE OF REVIEW: Several primary immune deficiency disorders are associated with autoimmunity and malignancy, suggesting a state of immune dysregulation. Here, we review the role of regulatory T-cell deficits in mediating the immune dysregulation associated with certain primary immune deficiency disorder syndromes. RECENT FINDINGS: Systematic studies in primary immune deficiency disorders and their associated animal models have led to an increased understanding of both central and peripheral tolerance mechanisms, and in particular have yielded new insights into regulatory T-cell function, development and maintenance. SUMMARY: Single-gene defects identified in patients with multiple autoimmune phenomena have defined new primary immune deficiency disorder syndromes in which the primary deficit is in the establishment or maintenance of immune tolerance. The disorder that has been most informative with regard to understanding the function and development of regulatory T cells is forkhead box P3 deficiency, known as immune dysregulation, polyendocrinopathy, enteropathy and X-linked syndrome in humans and Scurfy in the mouse. Recent studies in patients with other primary immune deficiency disorders, including autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy syndrome, CD25 deficiency, STAT5b deficiency, and Wiskott-Aldrich syndrome, have added to our understanding of regulatory T-cell biology. The study of patients with rare primary immune deficiency disorder syndromes provides an unparalleled opportunity to understand mechanisms of autoimmunity and immune tolerance in humans.     

Regulatory T cells in immunologic self-tolerance and autoimmune disease

Naturally arising CD25+ CD4+ regulatory T cells play key roles in the maintenance of immunologic self-tolerance and negative control of various immune responses. The majority, if not all, of them are produced by the normal thymus as a functionally distinct T-cell subpopulation, and their generation is in part developmentally controlled. Genetic abnormality in the development and function of this population can indeed be a cause of autoimmune disease, immunopathology, and allergy in humans. This regulatory population can be exploited to prevent and treat autoimmune disease by strengthening and reestablishing immunologic self-tolerance.     

Regulatory B cells in autoimmune diseases and mucosal immune homeostasis

B lymphocytes contribute to physiological immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their role in several autoimmune diseases, mainly as producers of pathogenic antibodies, is also well known. However, certain subsets of B cells are emerging as the important regulatory cell populations in both mouse and human. The regulatory functions of B cells have been demonstrated in a variety of mouse models of autoimmune diseases including collagen-induced arthritis (CIA), experiment autoimmune encephalomyelitis (EAE), anterior chamber-associated immune deviation (ACAID), diabetes, contact hypersensitivity (CHS), and intestinal mucosal inflammation. Accumulating evidence from both mouse and human studies confirms the existence of regulatory B cells, and is beginning to define their mechanisms of action. In this article, we first review the history of B cells with regulatory function in autoimmune diseases, and summarize the current understanding about the characterizations of such B-cell subsets. We then discuss the possible regulatory mechanisms of B cells, and specifically define the role of regulatory B cells in immune homeostasis in the intestine.     

Regulatory T cells protect from autoimmune arthritis during pregnancy

Pregnancy frequently has a beneficial effect on the autoimmune disease Rheumatoid Arthritis, ranging from improvement in clinical symptoms to complete remission. Despite decades of study, a mechanistic explanation remains elusive. Here, we demonstrate that an analogous pregnancy-induced remission can be observed in a mouse model of arthritis. We demonstrate that during pregnancy mice are protected from collagen-induced arthritis, but are still capable of launching normal immune responses to influenza infections. We examine the role of regulatory T (T(R)) cells in this beneficial effect. T(R) cells are essential for many aspects of immune tolerance, including the suppression of autoimmune responses. Remarkably, transfer of regulatory T cells from pregnant 'protected' mice was sufficient to confer protection to non-pregnant mice. These results suggest that regulatory T cells are responsible for the pregnancy-induced amelioration of arthritis.     

Regulatory T cells and inflammatory bowel diseases]

Crohn's disease and ulcerative colitis are two major forms of human inflammatory bowel diseases (IBD). Their etiology is unknown, but increasing evidence indicate that immune mechanisms play an important role. It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T (TR) cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of IBD. This article reviews the unique aspects of TR cells and discuss how these control the intestinal homeostasis.