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Role of Regulatory T Cells in Rheumatoid Arthritis: Facts and Hypothesis

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Role of Regulatory T Cells in Rheumatoid Arthritis: Facts and Hypothesis Autoimmun Highlights (2010) 1:45–51 DOI 10.1007/s13317-010-0008-2 REVIEW ARTICLE Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis Alessia Alunno • Elena Bartoloni • Giuseppe Nocentini • Onelia Bistoni • Simona Ronchetti • Maria Grazia Petrillo • Carlo Riccardi • Roberto Gerli Received: 01 April 2010 / Accepted: 06 April 2010 / Published online: … … … © Springer-Verlag 2010 Abstract Regulatory T cells (Treg) are a CD4+ lympho- Introduction cyte subset involved in self-tolerance and autoimmunity prevention. There is evidence for a phenotypic and/or Regulatory T (Treg) cells are a specialized CD4+ lym- functional impairment of this cell subset during the natu- phocyte subset able to modulate immune response to ral history of several chronic autoimmune/inflammatory environmental pathogens as well as to prevent immune diseases, including rheumatoid arthritis (RA). Although responses against inappropriate targets, including self the intracellular transcription factor FoxP3 is thought to antigens [1]. In fact, Treg cells can suppress autoreactive be the master regulator of Treg cell function, a number of lymphocyte clones that have escaped the negative selec- other molecules expressed on the cell surface have been tion in the thymus by different mechanisms, thus prevent- proposed for the identification of Treg cells. This is ing the activation and expansion of these effector cell important in order to favour their possible selective isola- subsets. Suppression can be either in a cell–cell contact tion and in the development of new therapeutic strategies. manner or via soluble factors produced by Treg cells In the present paper, available data on phenotypic and themselves [2, 3]. functional characterization of Treg cells in both peripher- The well-known role played by T cells in the develop- al blood and synovial fluid from RA patients are reviewed ment of autoimmunity was characterized in the mid- and their possible pathogenic role in triggering and per- 1990s by Sakaguchi et al. who demonstrated that a T-cell petuating rheumatoid joint inflammation is discussed. subset expressing high levels of IL-2 receptor α-chains (CD25) was able to prevent the onset of systemic autoim- Keywords Treg cells · Rheumatoid arthritis · FoxP3 · mune diseases in thymectomized mice [4]. The high sur- GITR face expression of the CD25 molecule, in association with the intracellular expression of the forkhead winged- helix transcription factor Foxp3 (forkhead fox p3), allows isolation of Treg cells also in human peripheral ౧ A. Alunno · E. Bartoloni · O. Bistoni · R. Gerli ( ) blood (PB) and the definition of Treg cells as Rheumatology Unit, + high + Department of Clinical and Experimental Medicine, CD4 CD25 FoxP3 has therefore been considered one University of Perugia, of their main phenotypic features [5]. via E. dal Pozzo, Perugia, I-06122, Italy The hypothesis that Treg cells could be involved in Tel.: +39-075-5783975 the pathogenesis of autoimmune diseases led to subse- Fax: +39-075-5783105 Email: [email protected] quent investigations not only in animal models with autoimmune disorders, but also in patients with such dis- G. Nocentini · S. Ronchetti · M.G. Petrillo · C. Riccardi eases in order to clarify the degree to which the Treg cells Section of Pharmacology, might be functionally impaired [6, 7]. Toxicology and Chemotherapy, Department of Clinical and Experimental Medicine, With regard to their origin, Treg cells can be divided University of Perugia, I-06122 Perugia, Italy into two main populations with similar phenotypes but 46 Autoimmun Highlights (2010) 1:45–51 different developments. Natural Treg cells are generated now well accepted that Foxp3, despite being a distinctive in the thymus in the early years of life and show the abil- marker for Treg cells, can also be expressed by human ity to bind self antigens by their T-cell receptor. They are effector T cells after activation [17]. However, its expres- distinguished from adaptive Treg cells that are induced in sion on T cells is transient, occasional, and never as high the PB throughout life by conversion of CD4+CD25− as in Treg cells. An intriguing finding is that FoxP3-pos- naive T cells in the presence of a particular cytokine itive T-cell populations with absent, or at least low, sur- microenvironment [8–10]. face expression of CD25 (CD25−/low), areabletoexertan Although Treg cells could be considered a simple in vitro suppressive activity towards effector T cells, population of suppressor T cells, it has been shown that thereby displaying a regulatory function [18]. Such a cell they are more heterogeneous and play a pivotal role in subset seems to be increased in patients with autoim- the maintenance of immune tolerance. They can exert mune diseases such as systemic lupus erythematosus their suppressive activity via different mechanisms in compared to normal controls, but no data have been pub- order to eliminate autoreactive effector lymphocyte lished so far on rheumatoid arthritis (RA) [19]. clones. In particular conditions which allow cell–cell Further studies are required to better characterize its contact, Treg cells are able to trigger apoptotic pathways phenotypic and functional features. In this setting, our that lead to the death of effector cells. On the other hand, group is assessing the functional activity of CD25−/low they secrete soluble molecules such as IL-10 and TGF-β cells expressing FoxP3 as well as high levels of GITR on which restore an antiinflammatory milieu and thus block the cell surface. The aim of our study was to better char- the stimuli for effector cells. acterize this supposed regulatory CD25−/low subset and to Although Treg cells were identified in early studies investigate the possible role of GITR as a specific mark- by their surface expression of CD4 and high levels of er of Treg cells also in humans, as mentioned above. CD25, additional surface molecules have subsequently been proposed as specific Treg cell markers, including cytotoxic T lymphocyte antigen-4 (CTLA-4), CD127 and The paradox of Treg cell expansion in RA patients glucocorticoid-induced TNF receptor-related protein (GITR) [11, 12]. GITR is a well-known marker of Treg The hypothesis that Treg cells may play a key role in the cells in mice, but little is known about its role in humans. pathogenesis of autoimmune diseases has been tested by Unfortunately, the fact that CD25, CTLA-4, and GITR several groups. Plenty of data have been published on are also upregulated on the surface of activated T cells Treg cell numbers and function in different human chron- makes the interpretation of some experimental data diffi- ic inflammatory diseases [20–26]. RA is a systemic cult in healthy subjects as well as in patients. The discov- inflammatory disorder characterized by chronic synovial ery of Foxp3 as master regulator for Treg cells added a inflammation resulting in cartilage and bone damage key marker for this T-cell subset. Foxp3, previously eventually leading to joint destruction. The aetiology and called JM2, was first characterized as the target gene pathogenesis of RA are not fully understood, although mutated in a murine autoimmune syndrome (X-linked breakdown of self-tolerance is a hallmark of the disease. autoimmunity-allergic dysregulation syndrome) and was Several studies have been carried out with the aim of subsequently related to the human counterpart of this clarifying whether Treg cell dysregulation could be syndrome (immunodysregulation polyendocrinopathy involved as a disease trigger and/or in maintenance of the enteropathy X-linked syndrome) [13, 14]. disease, and in an attempt to shed some light on possible Further studies following Treg cell isolation have underlying mechanisms by which this dysregulation shown that this transcription factor is constitutively occurs. Early evidence came from studies performed on expressed at high levels in both natural and adaptive murine models of inflammatory arthritis, such as colla- CD4+CD25high Treg cells in humans and mice. Foxp3 is gen-induced arthritis (CIA) [27]. It has been shown that required for the natural Treg cell lineage commitment in mice depleted of CD4+CD25+ cells develop a more the thymus and it is essential in stabilizing and amplify- severe arthritis and higher titres of anticollagen antibod- ing a Treg cell program, inclusive of anergy and defective ies [28]. On the other hand, a single transfer of IL-2 production, induced by interaction of Treg cell pre- CD4+CD25+ Treg cells into mice exhibiting arthritis cursors with stromal cells in the thymus [14, 15]. symptoms is able to markedly slow disease progression Furthermore, recent investigations on induced Foxp3 [29]. Moreover, the above-mentioned marker of murine expression in activated CD4+CD25− T cells have shown Tregcells,GITR,hasbeenshowntobeinvolvedinthe that the presence of Foxp3 at high levels as well as the development of CIA, as demonstrated by a reduced sus- persistence of its expression are fundamental for main- ceptibility to CIA of GITR-deficient mice [30]. The abo- taining suppressor function [15, 16]. Interestingly, it is lition of GITR signalling in effector T cells is able to Autoimmun Highlights (2010) 1:45–51 47 reduce the severity of arthritis because of the lack of acti- confirmed higher numbers of circulating Treg cells in vation stimuli triggered by this pathway [30]. patients with long-standing disease [35, 39]. Moreover, Initial studies performed in RA patients investigated in established disease, where proinflammatory cytokines, Treg cell phenotype in PB and synovial fluid (SF) with the including TNFα, are present at high levels in PB and tar- aim of also evaluating possible imbalance of Treg cell get organs, FoxP3 expression within the CD4+CD25+ cell number in human chronic inflammatory diseases [31, 32]. population seems to be reduced, giving rise to the As summarized in Table 1, conflicting data have been pub- hypothesis that proinflammatory molecules play a role in lished so far regarding the percentages CD4+CD25+ cells inducing an abnormal Treg cell phenotype [37, 40].
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