IntroductionImmunologic self-tolerance is critical for the prevention of autoimmunity and maintenance of immune homeostasis. The ability of the immune system to discriminate between self and nonself is controlled by central and peripheral tolerance mechanisms. The former involves deletion of self-reactive T cells in the thymus at an early stage of development, 1,2 whereas peripheral tolerance involves several mechanisms, including T-cell anergy and ignorance. Since these mechanisms are not completely effective and potentially autoantigen-reactive lymphocytes escape into the periphery, additional mechanisms are involved in the maintenance of self-tolerance. A number of subsets of regulatory T cells play an important role in preventing activation of autoantigenreactive T cells. Among these are naturally occurring "professional" regulatory T cells (Tregs). In this regard, studies carried out during the past decade provided strong evidence for the existence of a unique CD4 ϩ CD25 ϩ population of naturally occurring regulatory/suppressor T cells that actively prevent both the activation and the effector function of autoreactive T cells that have escaped other mechanisms of tolerance. [3][4][5] Removal of this population from normal rodents leads to the spontaneous development of various autoimmune diseases, organ specific as well as systemic. Notably, the generation of CD4 ϩ CD25 ϩ T-regulatory cells in the immune system is developmentally and genetically controlled, as recent studies have demonstrated that the transcription factor, FoxP3, is essential for their thymic development 6 and is sufficient to activate a program of suppressor function in peripheral CD4 ϩ CD25 Ϫ T cells. 7 Genetic defects that affect the development or function of CD4 ϩ CD25 ϩ Tregs can be a primary cause of autoimmune and other inflammatory disorders in humans. 8 It has been proposed that during the initiation of an adaptive immune response, dendritic cells can induce effector CD4 ϩ T cells to become resistant to the suppressive effects of Tregs by secreting IL-6, thus allowing a productive immune response to take place. 9 Similarly, glucocorticoid-induced tumor necrosis factor-like receptor (GITR) engagement on effector T cells by its ligand (GITRL) expressed on antigen-presenting cells (APCs) has been claimed to render them resistant to suppression by CD4 ϩ CD25 ϩ Tregs, 10 and may also have an effect on the function of Tregs. 11 Recent studies have revealed the presence of CD4 ϩ CD25 ϩ Tregs in human peripheral blood, where they constitute up to 5% of the CD4 ϩ T cells. 12,13 These cells are similar to those described in the mouse in that they require cell-to-cell contact to exert their suppressive effect. Whether a soluble factor is involved depends on the experimental system used. 14,15 Tumor necrosis factor (TNF) is a pleiotropic cytokine critical for cell trafficking, inflammation, maintenance of secondary lymphoid organ structure, and host defense against various pathogens. 16 Because of this panoply of effects, TNF plays a critic...

CD4+CD25+ T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4+CD25high Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE. In this study, we report a significant decrease in the suppressive function of CD4+CD25high Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE. Notably, CD4+CD25high Tregs isolated from patients with active SLE expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4+ effector T cells in vitro. In contrast, the expression of FoxP3 mRNA and protein and in vitro suppression of the proliferation of CD4+ effector T cells by Tregs isolated from inactive SLE patients, was comparable to that of normal individuals. In vitro activation of CD4+CD25high Tregs from patients with active SLE increased FoxP3 mRNA and protein expression and restored their suppressive function. These data are the first to demonstrate a reversible defect in CD4+CD25high Treg function in patients with active SLE, and suggest that strategies to enhance the function of these cells might benefit patients with this autoimmune disease.

Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti–cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11–Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA.