importance of regulatory t cells in the pathogenesis of psoriasis: review of the literature

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Dermatology DOI: 10.1159/000353398

Importance of Regulatory T Cells in the Pathogenesis of Psoriasis: Review of the Literature

Carlo Mattozzi Monica Salvi Sara D’Epiro Simona Giancristoforo

Laura Macaluso Cecilia Luci Karan Lal Stefano Calvieri

Antonio Giovanni Richetta

Department of Dermatology and Venereology, University of Rome, Rome, Italy

Introduction

Psoriasis is a common chronic relapsing inflammatory cutaneous disease characterized by thickened, scaly skin patches, caused by abnormal keratinocyte proliferation, vascular hyperplasia and infiltration of inflammatory cells into the dermis and epidermis [1] , and leads to a con-siderable impairment of the quality of life in affected pa-tients. The prevalence varies from 1 to 4% of the world’s population, and its genesis is multifactorial [2] .

Several hypotheses have been postulated to explain the pathogenesis of this disorder; in the past, psoriasis was considered a disease due to an accelerated turnover of ke-ratinocytes; instead, however, recent studies point out the pivotal role of lymphocytes in the pathogenesis of this disorder [3] .

Components of innate immunity, such as dendritic cells, natural killer (NK) T cells, neutrophilic granulo-cytes and macrophages, as well as T lymphocytes, CD8+ and CD4+ (T helper 1, Th1; Th17), representing acquired immunity, contribute equally to the immune response in psoriatic lesions [4, 5] .

It is not clear whether the disease arises from keratino-cytes or from lymphocytes, but the efficacy of immuno-

Key Words

Regulatory T cells · Psoriasis · Innate immunity

Abstract

Psoriasis is a common chronic relapsing inflammatory cuta-neous disease; the main role in the inflammation of this con-dition is played by lymphocyte Th1, Th17 and their cyto-kines. The activity of these cells is modulated by a particular kind of T cells recently described: the T regulatory cells (Treg). These are able to inhibit the immunological response and to maintain the cutaneous immunological homeostasis, thus preventing autoimmunity against self antigens. Few data are available in the literature as to Treg in psoriasis; several studies demonstrate that the function of these cells is im-paired in this condition and treatments for psoriasis may in-crease the number and activity of Treg. The role of these cells in the pathogenesis of psoriasis is very important to under-stand how they may contribute to the development of this cutaneous disorder. In the near future it would be possible to target therapies at these defects, improving the activity of these cells and maintaining cutaneous homeostasis, pre-venting psoriasis or other inflammatory cutaneous condi-tions. © 2013 S. Karger AG, Basel

Received: December 5, 2012 Accepted after revision: May 6, 2013 Published online: September 14, 2013

Carlo Mattozzi Department of Dermatology and Venereology, University of Rome ‘Sapienza’Viale del Policlinico, 155IT–00133 Rome (Italy)E-Mail carlo.mattozzi @ gmail.com

© 2013 S. Karger AG, Basel1018–8665/13/0000–0000$38.00/0

www.karger.com/drm

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Mattozzi et al. DermatologyDOI: 10.1159/000353398

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suppressants and immunomodulator drugs such as cy-closporine, methotrexate and biological therapies [6] point out the important role of these cells and their cyto-kines in the pathogenesis of psoriasis.

The pathophysiology of inflammation within this con-dition is based on lymphocytes Th1, Th17 and their cyto-kines [tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6, IL-8, IL-12, IL-22 and IL-23], and the interplay between these cells, keratinocytes and antigen-presenting cells (APC) may induce and maintain abnor-mal and defective epidermal growth [7] .

The activity of these cells is modulated by a particular kind of T lymphocytes recently described: the regulatory T cells (T reg ). These cells are able to inhibit the immuno-logical response and maintain the cutaneous immuno-logical homeostasis, just preventing the autoimmune re-sponse against self-antigens. They are involved in several autoimmune diseases such as multiple sclerosis (MS), type I autoimmune diabetes, inflammatory bowel diseas-es (IBD), severe allergy including atopic dermatitis, rheu-matoid arthritis, polyendocrinopathy syndrome type II (APC II), immune dysregulation, polyendocrinopathy, enteropathy and X-linked syndrome and psoriasis [8] .

This review analyzes the role of the T reg cell in the pathogenesis of psoriasis.

Regulatory T Cells

CD4+Foxp3+ regulatory T lymphocytes (T reg ) are a subclass of CD4+ T cell receptors (TCR) αβ+ and are es-sential to preserve immune homeostasis. Absence of T reg or the Foxp3 transcription factor they express leads to the rapid development of fulminant multiorgan autoimmu-nity, and this condition has been demonstrated in mice in which the absence of T reg cells, or their depletion, resulted in the development of autoimmune gastritis, thyroiditis, diabetes and IBD [9, 10] .

Several studies in animal models show that defects in CD4+CD25+Foxp3+ T cells are responsible for the devel-opment of autoimmunity and that the replacement of T reg with adoptive transfer of these cells is able to reverse this multifaceted condition [11] . The important role in the maintenance of immunological homeostasis in humans is highlighted by the severe inflammation and autoim-munity that occurs in individuals who suffer from immu-nodysregulation, polyendocrinopathy, enteropathy and X-linked syndrome. In fact these individuals develop sev-eral autoantibodies and autoimmune diseases due to the absence of regulation of the immune system by T reg cells,

and without bone marrow transplant they die at a young age [9] .

Unlike other CD4+ T cell subsets that differentiate ex-trathymic from conventional CD4+ T cells, T reg can de-velop as a separate population in the thymus. For this rea-son, T reg cells are often considered as a distinct cellular lin-eage. Yet the extent to which these cells are an independent lineage or a metastable maturation state, interconvertible with conventional T cells, has to be elucidated [12, 13] .

The T reg have shown a high degree of stability with pre-served phenotypic and functional properties and an acute sensitivity and adaptability to environmental inputs.

Circulating T reg cells include 2 main populations: a thymically derived one that appears to meet the criteria for a cellular lineage, and a second that forms adaptively and seems not to meet the specific criteria.

The first population type is represented by natural T reg (nT reg ) that arise in the thymus during early stages of hu-man fetal development (gestational week 14) and are re-sistant to thymic deletion. nT reg differentiate from thy-mocytes that express TCRs with an increased affinity for self-peptide-major histocompatibility complexes; there they differentiate and express CD25, the α-chain of the IL-2 receptor and Foxp3. The second type is another pop-ulation that is induced by environmental antigens and extrathymic signals that can upregulate Foxp3 in conven-tional T cells (a Foxp3– population), converting them into induced T reg (iT reg ), CD4+CD25+ cells that are in-duced from CD25– precursors in peripheral lymphoid organs [14, 15] .

nT reg and iT reg cells have a similar phenotype and are able to modulate inflammation by several mechanisms of action that are not completely known. nT reg cells express T cell activation/differentiation markers [CD45RO (mem-ory phenotype; activated), CD45RB (resting), CD25 (both)], adhesion molecules [CD62L (both), CD44 (both) and integrin α4β7 (resting)], cytotoxic T lymphocyte-as-sociated protein-4 (CTLA-4; both), costimulatory mole-cule CD28 (both), chemokine receptors [CCR7 (both), CXCR4 (both), CCR9 (resting)], glucocorticoid-induced TNF receptor-related protein (both), OX40 (CD134, both), and folate receptor-4 (in rodents, both) [16] . iT reg are induced by IL-2 and transforming growth factor β (TGF-β) and they show a similar phenotype, but they dif-fer from nT reg because they are generated from naïve CD4+ cells and require additional stimulation to develop memory markers. The few CD4+CD45RA+CD25+ cells in the naïve fraction, however, have the highest regenera-tive capacity [17] and can markedly enhance the numbers of CD4+CD25– cells that become CD25+ iT reg .

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Importance of Regulatory T Cells in the Pathogenesis of Psoriasis

DermatologyDOI: 10.1159/000353398

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Although IL-2 and TGF-β are required only for the generation of iT reg , both of these cytokines are needed for the maintenance of Foxp3 expressed by nT reg and iT reg [18] ; Foxp3 expression by nT reg is, however, more stable than that by iT reg cells, possibly because these cells are be-ing continuously stimulated by self-antigens. Foxp3 ex-pressed by mouse and human iT reg rapidly decays in the absence of both of these cytokines [19, 20] .

The action of T reg is directed mainly against T cells and/or dendritic cells – these cells may be inhibited by 3 main regulatory model processes: (1) cytokines; (2) direct inhibition (cell-to-cell contact), and (3) competition for growth factors.

TGF-β has direct suppressive effects on effector T cells, while IL-10 indirectly works via inhibition of APC matu-ration [21] . Fibrinogen-like protein-2 is able to induce apoptosis on effector T cells and prevents maturation of dendritic cells [22] . Granzyme A/B and perforin have apoptotic effects on effector T cells [23] and the produc-tion of adenosine by CD39/73 cleavage of ATP causes cell cycle arrest in effector T cells and prevents their matura-tion. Furthermore, it decreases the antigen-presentingcapability in dendritic cells by binding to the A2A recep-tor on these cell types [24] . Galectin-1 binding to effector T cells and dendritic cells may arrest the cell cycle and/or may induce apoptosis [25] , CTLA-4 and CD80/86 bind-ing to dendritic cells causing decreased costimulation and decreased antigen presentation [26] ; lymphocyte-activat-ing gene-3 (CD223, a CD4 homolog) prevents matura-tion and reduces the capability to present antigen in den-dritic cells binding to major histocompatibility complex II molecules [27] ; neuropilin-1 is able to decrease antigen presentation binding to dendritic cells [28] . These are ex-amples of mechanisms by which T reg may downmodulate the immune system by a cell-to-cell contact inhibition. T reg can also act just preventing the contact between sol-uble factors and other inflammatory cells, such as T cells and dendritic cells, by binding and depriving soluble modulators leading to an inhibition of the immune sys-tem – this model has been demonstrated for IL-2 leading to effector T cell apoptosis [29] . Therefore, T reg cells have a variety of mechanisms that can be used to suppress an immune response and are able to use all or a subset of these mechanisms simultaneously ( table 1 ).

nT reg are thymus-derived CD4+CD25+Foxp3+ T cells and can suppress the following cell types: CD4+ T cells, dendritic cells, CD8+ T cells, NK T cells, NK cells, mono-cytes/macrophages, B cells, mast cells, basophils, eosino-phils, and osteoblasts [30, 31] .

iT reg cells instead are divided into two common cellular types: T regulatory type 1 cells (Tr1) and Th3 T reg cells. Tr1 cells are able to produce high levels of IL-10 and TGF-β in the human and mouse and also secrete low levels of IL-2, IL-5, IFN-γ and IL-15, that can support Tr1 cellular pro-liferation even without TCR activation [32, 33] .

The inhibitory activity of Tr1 is carried out by soluble mediators and this can be negated in the presence anti-IL-10 antibodies in vitro [32, 33] .

Th3 cells secrete mainly TGF-β that is fundamental for their induction from CD4+-naïve T cells and prolifera-tion. They play a pivotal role in oral tolerance to non-self-antigen and autoimmune conditions [34, 35] . Their regu-latory activity is due mainly to cytokine production (i.e.

Table 1. Summary of the 3 main regulative model processes used by Treg cells to modulate or to suppress the immune response

CytokinesIL-10 Suppressive effects on effector T cells via

inhibition of APC maturationTGF-β Direct suppressive effects on effector T cellsFLG-2 Apoptotic effect on effector T cells

Prevents maturation of dendritic cellsGranzyme A/B Apoptotic effects on effector T cellsPerforin Apoptotic effects on effector T cellsAdenosine Cell cycle arrest in effector T cells

Prevents their maturationDecreases antigen-presenting capability in dendritic cells

Cell-to-cell contactGalectin-1 Binding to effector T cells and dendritic cells

may arrest cell cycle and/or induce apoptosisCTLA-4 Binding to dendritic cells causes decreased co-

stimulation and decreased antigen presentationCD80/86 Binding to dendritic cells causes decreased

costimulation and decreased antigen presentation

LAG-3 Binding to MHCII molecules prevents maturation and reduces capability to present antigen in dendritic cells

Neuropilin-1 Binding to dendritic cells decreases antigen presentation

Competition for growth factorsIL-2 and other cytokines

Effector T cell apoptosis

FLG-2 = Fibrinogen-like protein-2; LAG-3 = lymphocyte-acti-vating gene-3; MHCII = major histocompatibility complex II.

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TGF-β), and they have a reciprocal relationship with Th17 cells [36] ( fig. 1 ).

Other T cell populations that have been shown to have regulatory function include inducible CD8+ T reg cells, CD8+CD28– T reg cells, and CD3+CD4–CD8– T reg (dou-ble-negative), CD4+Vα14+ (NK T reg ) and γδ T cells (mu-cosal/intraepithelial). Recently a particular subset of B cells with regulatory function has been described: the reg-ulatory B cell [37] .

A pivotal role in the development and function of T reg is played by Foxp3, a forkhead box transcription factor, a molecular marker and cell lineage specification factor for T reg . Foxp3 is fundamental for thymic differentiation of nT reg and its product of translation regulates a set of genes required for the suppressor activity of T reg , proliferative, and metabolic fitness of T reg and represses alternative T cell differentiation pathways [10, 38] . A high level of the transcription of this gene is able to confer inhibitory ac-tivity in non-T reg T cells in rodents [39] . Levels of Foxp3 are increased by several cytokines such as IL-2, TGF-β, retinoic acid, 17-β-estradiol, and signaling through the sphingosine-1-phosphate receptor 1 [39] .

In mice a frameshift mutation in the Foxp3 gene is re-sponsible of a ‘scurfy’ phenotype that is lethal in hemizy-gous males after birth for an overproliferation of CD4+T lymphocytes and other cell types due to uncontrolled cytokine secretion with extensive multiorgan infiltration due to lack of functional T reg cells [40] .

T reg cells were first defined on the basis of their expres-sion of CD25, which forms part of the high-affinity IL-2 receptor. Furthermore, CD25 is also expressed by re-cently activated T cells, resulting in the inclusion of CD4+CD25+ effector T cells in the T reg cell population. With the discovery that expression of Foxp3 has a central role in the differentiation and maintenance of T reg cells [41] , the use of flow cytometry-based analysis of Foxp3 expression in T cells has become the gold standard for defining T reg cells. However, it then has become evident that Foxp3 can also be expressed by effector T cells fol-lowing activation [42] , raising the possibility that any as-sessment of T reg cell number or function may include re-cently activated effector T cells in the T reg cell population. Furthermore, as Foxp3 is a nuclear protein, assessment of its expression in T cells requires fixation and permeabili-zation of the cells, resulting in an inability to obtain viable cells for further functional analysis. In the past few years, additional markers, such as CD127 (also known as IL-7Rα) [43] , have been identified that assist in the distinc-tion of effector T cells from T reg cells and facilitate the experimental purification of T reg cells. Phenotypes are de-termined using direct immunofluorescence with a panel of monoclonal antibodies directed against the following antigens: CD45, CD3, CD4, CD8, CD14, CD19, CD16, CD25, CD56, CD11b, CD45RA, CD45RO, CD12 and Foxp3 [44] .

Thymus

Peripheraldifferentiation

Tr1 Th3 Th2 Th1 Th17(CD4+CD25+FOXP3–)

(CD4+CD25+FOXP3+)

CD4+

Th0CD4+

CD4+ CD4+iTreg

(CD4+FOXP3+)

nTreg(CD4+CD25+FOXP3+)

Fig. 1. Differentiation of T reg from thymus (nT reg ) or from naïve T cells (Th0) in the periphery (iT reg ). Types of iT reg include Th3, Tr1, which are CD4+CD25+Foxp3+, and CD4+CD25–Foxp3+ iT reg . From Th0 may develop effector T cells that are repre-sented by Th1, Th2 and Th17. Furthermore in this figure are listed some of the impor-tant cytokines involved in the differentia-tion of iT reg and effector T cells from Th0 and the cytokines that these cells secrete. GM-CSF = Granulocyte-macrophage colo-ny-stimulating factor; G-CSF = granulo-cyte colony-stimulating factor.

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Impaired T Cell Suppression

T reg cells are fundamental in immune homeostasis, and alteration of their function is responsible for impos-sible downregulation of immune response and autoim-mune diseases.

There are several mechanisms by which T reg cells are not able to regulate the activation of T cells and dendritic cells, and this can be made evident by examining their main regulatory model processes and their presence in serum and tissues.

Defects in the number and function of T reg cells, as well as a resistance of effector T cells to T reg cell-mediated sup-pression, could each contribute to failed T cell regulation. Each of these defects has been shown to contribute to the development of autoimmunity in various model systems.

The reason for this phenomenon can be found in sev-eral cellular lineages and in their response to inhibitory messages. Cell-intrinsic defects in effector T cells, CD4+ Foxp3+ T cells and APCs, as well as alterations in the composition of the inflammatory milieu, can contribute to failed tolerance to self.

T reg regulation in autoimmunity might be effected by alteration of numbers of T cells, an impaired regulatory model process and multiple mechanisms by which effec-tor T cells resist T reg cells.

Evidence that an inadequate number of T reg may be responsible for developing autoimmune diseases is dem-onstrated in mouse models by the occurrence of aggres-sive autoimmunity in scurfy mice and is indirectly im-plied by the successful treatment of autoimmunity in mice through the adoptive transfer of wild-type T reg cells [9, 11] . The number of T reg cells is regulated by their de-velopment, persistence and proliferation in the periphery and homing to the sites of inflammation. In this condi-tion genetic factors seem to have an important role in the thymic output of T reg cells. The regulation of their num-ber in the periphery is a dynamic process influenced by conditions that support their induction, proliferation and survival. The thymic output and survival of T reg cells is regulated by factors that increase the expression of Foxp3, which includes CD28, TGF-β, dendritic cells and the common cytokine receptor γ-chain cytokines (IL-2, IL-4, IL-7 and IL-15), which signal through signal transducers and activators of transcription 5 [45–47] .

T reg cell dysfunction is difficult to understand and to demonstrate in vivo; for this reason it is necessary in in vivo models to evaluate the activity of these cells in an inflam-matory condition. As previously mentioned, T reg impaired activity is the result of the defect of one or several of the

many mechanisms of action of these cells. This could occur in conditions in which there is an inadequate expression of cell surface molecules involved in response to inhibitory cytokines or in cell-to-cell modulation (such as CTLA-4, CD39, lymphocyte activation gene 3, granzyme A and CD95, also known as FAS) or as a result of reduction in the ability to produce the soluble factors (such as TGF-β, IL-10 and IL-35) that are involved in some aspects of suppression [48] . Genetic factors might be involved in these mecha-nisms and the composition of local immune conditions may influence the action of T reg cells.

Another mechanism by which there is an impaired ac-tion of T reg cells is due to effector T cell resistance to in-hibitory signals. Cell-intrinsic resistance to suppression has been shown to occur in CD4+ memory T cells and Th17 cells [49] . IL-2, IL-4, IL-7 and IL-15 support the proliferation of effector T cells avoiding the inhibitory signals of T reg , indicating that these cytokines in the short term allow effector T cells to bypass suppression by T reg cells. In addition, several members of the TNF receptor family have been implicated in this process. Antibodies specific for OX40 (also known as TNFRSF4) abrogate suppression when bound to effector T cells [50] , and liga-tion of 4-1BB (also known as TNFRSF9) results in sup-pression-resistant effector T cells [51] .

T reg and Autoimmune Diseases

Impaired activity of T reg is involved in several autoim-mune diseases. The modulation of effector T cells is fun-damental in homeostasis of immune response and in de-letion of anti-self T cells. In autoimmune diseases usually T reg cells are impaired in numbers or in a model system of inhibition and in this condition autoreactive T andB cells may contribute to an immunological response against self-antigens and develop autoimmune disorders. T reg impaired function may be involved in multiorgan immune response and this condition might contribute to excessive tissue damage.

The role of numbers of T reg cells in autoimmune con-ditions has been demonstrated for several immune-me-diated diseases and the importance of their function has been shown in several studies in which immunosuppres-sive therapies increase their count.

T reg cell impaired function is implicated in many auto-immune diseases such as: type I diabetes, MS, systemic lupus erythematous (SLE), rheumatoid arthritis, IBD and several cutaneous autoimmune diseases.

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Type I diabetes is an autoimmune disorder in which there is a progressive destruction of pancreatic islet pa-renchyma. In NOD mice T reg cells decrease with the pro-gression of the disease and T effector cells were shown to become resistant to suppression and that the transfer of T reg cells, or treatment with IL-2, ameliorated the disease [52–54] .

The count of T reg cells in diabetic patients is an issue of controversy; initial analyses reported a significant de-crease in CD4+CD25+ T reg cell numbers [55] , while oth-er studies have found no differences [56, 57] . Studies have demonstrated a reduced capacity of T reg cells to respond to IL-2 (defect in IL-2 receptor signaling in CD4+CD25+ T cells) [58] and an inadequate number of T reg cells in the islets of individuals with type I diabetes [59] . Finally it has also been discovered that there is intrinsic effector T cell resistance to suppression by T reg cells in type I diabetes [60, 61] .

MS is an autoimmune disease characterized by inflam-matory lesions and degeneration of the central nervous system. Model mice develop MS in the absence of T reg cells, and the adoptive transfer of T reg cells reduces the incidence of this condition [41, 62] .

In most studies no differences of their numbers were found in the blood of patients afflicted by MS and con-trols [63–65] , but the number of T reg cells has been found to be increased in the cerebrospinal fluid [65] . Some stud-ies have shown that the numbers of T reg cells in MS and their modification following treatment with IFN-β [66–68] have been altered. Recent studies have reported a de-crease in the naïve cells or a decrease in recent thymic immi gration of T reg cells [68–70] and in the percentage of CD4+CD25hi cells that express CD39 [70] , a molecule has been linked to T reg cell function in mice. Furthermore, an increase in the CD127+ population of Foxp3+ T reg cells, a subset that is not suppressive, has been reported [71] .

Studies have shown an impaired suppression ability of T reg cells, although no correlation between their function and disease activity has been identified [72, 73] .

Furthermore, studies have pointed out that the T reg cell ability to produce IL-10 is impaired [73] and effector T cells are resistant to suppression in MS [69, 72] .

SLE is an autoimmune disease characterized by auto-antibodies and immune complexes directed against sev-eral organs, including the skin, joints, kidneys and central nervous system. Several studies have shown that the per-centage of CD4+CD25hi cells is decreased in patients with SLE and that this decrease is inversely correlated with the disease activity [74–76] .

Despite the fact that several studies have found no im-paired function of T reg [77] , some authors have shown a reduction in activity of these cells [78] . Resistance of T effector cells to T reg in SLE has been investigated, but the results are controversial because several studies have not detected these defects [79, 80] , but two recent studies have shown that effector T cells can evade suppression in SLE [81, 82] .

Rheumatoid arthritis is an autoimmune disease in which the main target of inflammation is the synovium. Several studies have shown that T reg cells in peripheral blood are no different from that of controls [83–85] , but there is general agreement that the percentage of T reg cells is higher in the synovial fluid in patients with rheumatoid arthritis than in controls [83–85] . Despite some studies that have shown no differences in function of T reg in pa-tients with rheumatoid arthritis [84, 85] , recent groups have identified a focal defect in the production of IFN-γ and TNF in coculture assays [86] and in CTLA-4-medi-ated inhibition of T cell receptor signaling [87] .

Patients treated with anti-TNF-α-targeted therapy were found to have an increase in the number of periph-eral T reg cells [86] .

The term IBD is referred to a group of inflammatory conditions of the colon and small intestine. The two main types of IBD are ulcerative colitis and Crohn’s disease.

Studies have described an increase in CD4+CD25+ Foxp3+ T cells among individuals with Crohn’s disease [88, 89] , while other authors have found that the number of CD4+CD25hiFoxp3+ T cells was lower in patients with active IBD [90–92] . Studies from the gut have demon-strated an increase in T reg cells in the lamina propria and in mesenteric lymph nodes, particularly in and near in-flamed tissues [90, 91] .

Functional studies of T reg cells and response of T effec-tor cells to suppression have shown to be similar to that achieved by T reg cells from control individuals [93–95] .

Several studies have analyzed the role of T reg cells in cutaneous diseases suggesting that they may be involved in the pathogenesis of skin inflammation in autoimmune diseases.

Quaglino et al. [96] showed that absolute and percent-age values of the CD4+ CD25brightFoxp3+ cells were sig-nificantly reduced in bullous pemphigoid when com-pared with healthy controls and also showed a reduction of TGF-β and IL-10 serum levels and fewer circulating CD4+CD25brightFoxp3+ cells in patients with systemic sclerosis or morphea than in controls. The quantitative reduction of T reg cells, together with that of TGF-β and IL-10 serum levels, may be responsible for the loss of tol-

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erance observed in both systemic sclerosis and morphea [97] .

Dermatomyositis (DM) is an autoimmune disease of unknown etiopathogenesis primarily involving the skin and the muscles; however, this disease can occur in other organs as well including the heart and lungs. A study has investigated and characterized the number of T reg cells in the peripheral blood of patients with DM and compared results with other connective tissue diseases such as SLE, systemic sclerosis, and Sjögren’s syndrome as well as healthy controls. A reduced percentage of peripheral blood T reg cells was found in patients compared to con-trols, irrespective of the type of connective tissue disease [98] . Antiga et al. [99] investigated the frequency of CD4+CD25+ T reg cells in peripheral blood and their main effector cytokines in skin lesions and in serum from pa-tients with DM and compared the results with cutaneous lupus erythematosus, psoriasis, atopic dermatitis and healthy controls. The number of CD4+CD25+Foxp3+ T reg cells in the peripheral blood of patients with DM was significantly reduced compared to healthy controls,

whereas other cell populations showed no significant dif-ferences. Finally, TGF-β and IL-10 serum levels were sig-nificantly lower in patients with DM compared to healthy controls [99] .

T reg Cells and Psoriasis

Few data are available in the literature regarding T reg cells in psoriasis. Analyzing the role of acquired immu-nity and the activity of T effector cells in this disease, it is possible to conclude that an impaired activity and/or a reduced number of T reg cells might be involved in the pathogenesis of this cutaneous disorder, interfering with skin homeostasis and regulation of immune response. Surface expression of functional E- and P-selectin ligands is required for optimal migration of effector T cells to in-flamed skin; a high percentage of circulating human and mouse T reg cells express E- and/or P-ligands, and Foxp3+ T reg cells make up a large fraction of the CD4+ T cells in normal skin from both humans and mice [100, 101] ,

Neutrophils Neutrophils

Inflammatory DC

GeneticsPSORS1IL-23RNF- B

EnvironmentTraumaDrugsInfectionUV

Treg

Treg

Treg

Treg

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Fig. 2. Pathogenesis of psoriasis and the main cellular innate and acquired immunity and their cytokines involved in the develop-ment of psoriatic plaques. Environmental and genetic conditions may trigger the development of psoriasis just stimulating kerati-nocytes and dendritic cells and favoring the presentation of anti-gens to T cells and consequently the activation of acquired immu-nity. In this figure is highlighted the role of T reg in the modulation of inflammation inhibiting the activity of dendritic cells and Th1,

Th17 and Th22 lymphocytes. PSORS1 = Psoriasis susceptibility; NF-κB = nuclear factor κB; UV = ultraviolet; AMPs = antimicro-bial peptides; LC = Langerhans cell; ss-RNA = single-strand ribo-nucleic acid; KCs = keratinocytes; LL-37 = C-terminal part of the only human cathelicidin identified to date called human cationic antimicrobial protein (hCAP); KGF = keratinocytes growth factor; EGF = epidermal growth factor; NGF = nerve growth factor; DC = dendritic cell; pDC = plasmacytoid dendritic cell.

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demonstrating that these cells might be involved in cuta-neous homeostasis even in the absence of infection or in-flammation.

In predisposed individuals, it is possible that several inflammatory triggers might not be sufficiently downreg-ulated by T reg cells favoring the development of inflam-mation and consequently psoriatic plaques.

Cytokines are also produced by various immune cells in the skin, including dendritic cells and macrophages, and they may be responsible for the recruitment of vari-ous inflammatory subsets of T cells to the skin and circu-lation, such as Th17 cells that produce IL-17 and TNF-α and Th22 cells that produce IL-22 [102] ; in addition to recruitment of inflammatory T cell subsets, increased numbers of Foxp3+ infiltrating cells were found in psori-atic plaques, and increasing levels correlated with disease severity [103] ( fig. 2 ). In the same study it has been dem-onstrated that in addition to elevated T reg cells, there is also an increased Th17:T reg ratio which was found to be correlated with disease severity, suggesting that an imbal-ance of these T cell subsets may limit T reg cell effectiveness [103] .

IL-17 secretion by CD4+ T cells was not found to be regulated by T reg cells, even though they exhibited sig-nificant inhibition on CD4+ T cell proliferation and IFN-γ production [103] . These findings provide new in-formation regarding the association between Th17 and T reg cells, which will further enhance our understanding of the pathogenesis of psoriasis.

Zhang et al. [104] have reported that CD4+CD25+ T cells differentiated in vitro from hematopoietic cells of patients with psoriasis are impaired in regulatory func-tion. The dysfunction of psoriatic CD4+CD25+ T cells may be due to inherent genetic programming passed down from bone marrow-derived hematopoietic cells [104] .

In contrast, 2 other studies have reported no statistical differences between the number of CD4+CD25+ T reg cells in the peripheral blood of psoriasis patients and con-trols [103] and even showed an increase in the number of T reg cells in psoriatic skin lesions and in peripheral blood [105] . It is possible that the phase of psoriasis in disease (active spreading disease vs. stable plaque psoriasis), the severity of the clinical picture (mild, moderate, severe) and the site of biopsy (center vs. margin of the plaque) account for the differences [106] .

T reg cells were found predominantly in the upper der-mis and epidermis, and expression of these cells in pso-riasis was found to be similar to that of eczema or to be reduced [107, 108] .

The importance of T reg cells in this disease has been examined in the peripheral blood and in the inflamed skin of patients. Several studies have obtained different results about the number of these cells in the blood. Yan et al. [108] have demonstrated that T reg cells are increased in peripheral blood and that their level positively corre-lates with disease severity. Despite this observation, Chen et al. [109] found that a relative imbalance favoring effec-tor T cells was present in both the peripheral blood and psoriatic skin lesions.

Our group has found that the number of T reg cells is decreased in peripheral blood of psoriatic patients and their level is increased by anti-TNF-α-targeted treatment [110] . Additional studies of T reg cells in patients treated with infliximab showed that T reg cell numbers were in-creased [111] and a more diverse TCR repertoire was present in the T reg cell populations [112] . Quaglino et al. [113] have analyzed the expression of several genes re-lated to the different T cell immune response polarization (Th1, Th2, Th17 and T reg ) and have correlated them with clinical response. At baseline they found that an upreg-ulation of Th1 and Th17 along with a downregulationof T reg subsets was apparent, while after treatment with etanercept a significant reversal of the Th1/Th17 activa-tion and a concomitant upregulation of Th2 and T reg sub-sets were found [113] . These findings, together with in vitro evidence, demonstrate that TNF-α strongly inhibits the suppressive functions of the CD4+CD25bright cells. Levels of T reg cells have been analyzed in both peripheral blood and skin by Chen et al. [109] , demonstrating high-er levels in stable or regressive lesions and a reduction in stable plaques.

Notwithstanding that there is no agreement about the effect of cyclosporine on T reg in psoriasis, we have report-ed 3 cases in which there was a reduction of the periph-eral blood levels of these cells that was inversely corre-lated with disease severity [114] . This phenomenon may be explained by the mechanism of action of cyclosporine itself on T cells. This drug is not selective and acts not only toward T reg cells, but also toward Th1 and Th17, inhibit-ing T cell response and leading to a clinical improvement in psoriatic lesions [114] . It inhibits IL-2 transcription by blocking TCR-triggering events. TCR triggering and IL-2 are both essential to the maintenance of the T reg popula-tion in peripheral blood [20] . Furthermore, cyclosporine reduces the production of IL-2 and may also prevent IL-2 receptor expression on the precursor cytotoxic T lym-phocyte [115] .

Narrow-band UVB and bath psoralen + ultraviolet A have been demonstrated to increase local levels of

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CD4+CD25brightFoxp3+ cells, favoring the modulation of inflammation and improving the clinical manifesta-tion of psoriatic patients [116, 117] .

The suppressor activity of T reg cells in both the periph-eral blood and lesional skin of patients with psoriasis is deficient with respect to their ability to suppress both au-tologous and control effector T cells [117] .

Sugiyama et al. [118] have demonstrated that the pro-liferative capacity of effector T cells of patients with pso-riasis is enhanced compared with control cells and this condition might contribute to the resistance of T lympho-cytes to the inhibition of T reg cells. Effector T cell and T reg cell populations of lesional skin have an increased cell surface expression of IL-6 receptor and levels of this cy-tokine are increased in psoriatic plaques, demonstrating that impaired regulation of inflammation might be attrib-uted to IL-6 [119] . This assumption has been demonstrat-ed in coculture of T reg and effector T cells taken from pso-riatic patients, with antibodies directed against IL-6 [120] . For this reason it is possible to conclude that this cytokine might enhance the resistance of effector T cells to T reg cell-mediated suppression and might also inhibit T reg cell function.

For these reasons, similar to other autoimmune dis-eases, it is possible to point out 2 main causes of impaired T reg cell-mediated suppression in psoriasis: impaired T reg cell function and resistance of effector T cells to suppres-sion.

Recent data point out the possibility that T reg cells of psoriasis patients could differentiate in vivo into Th17 cells, under proinflammatory conditions. T reg of patients with severe psoriasis, as compared with those of healthy controls, have an enhanced propensity to differentiate into IL-17A-producing cells on ex vivo stimulation [121] . Increased T reg cell differentiation in patients with severe psoriasis is associated with a high expression of levels of the Th17-associated transcription factor RORγt and en-hanced loss of Foxp3. Foxp3 can directly bind to RORγt and antagonize Th17 differentiation of T cells [122] . The balance between Foxp3 and RORγt may determine whether a T reg cell or Th17 differentiation program will be induced.

IL-23 strongly boosts T reg cell differentiation in pso-riasis patients, which is associated with enhanced loss of Foxp3 while leaving the high RORγt levels unaffected [121] . These findings suggest that T reg cells of patients with severe psoriasis are particularly prone to differenti-ate into IL-17A-producing cells and this data may suggest novel ways for immunotherapy.

Conclusion

Psoriasis is a chronic cutaneous inflammatory disease. New insight into the pathogenesis has demonstrated the important role of T reg cells in the development of this dis-order and is correlated with reduced inhibitory activities of these cells. They arise naturally in the thymus and com-prise about 5–10% of the mature CD4+ helper T cells in mice and in humans too. T reg cells play a fundamental role in the immune homeostasis and are involved in several autoimmune diseases such as type I diabetes, MS, SLE, rheumatoid arthritis, IBD and psoriasis.

In psoriasis, only limited studies on T reg cells are avail-able and give conflicting results.

They might contribute to the development of psori-atic lesions, and this condition may be due to a reduction in number of these cells, with a reduced ability to produce suppressive cytokines or there may be a ‘resistance’ of T effector cells to the inhibition of T reg cells.

Although there is no agreement towards the role of these cells in the pathogenesis of psoriasis, it is very im-portant to understand how they may contribute to the development of this cutaneous disorder. For this reason necessary studies must be conducted that aim to demon-strate how T reg cells may induce psoriasis, alter cutaneous homeostasis or not inhibit skin inflammation. This con-cept is very important because in the future it may be pos-sible to target therapies at these defects improving the ac-tivity of these cells and maintaining cutaneous homeosta-sis. By this way it would prevent psoriasis or other inflammatory cutaneous conditions and will decrease the natural course and progression of the disease.

Animal models suggest that an increase in T reg cell number at the site of inflammation is likely to be thera-peutic in autoimmunity. This could be achieved in hu-mans by adoptive transfer of in vitro expanded autolo-gous T reg cells or by the use of agents that promote T reg cell proliferation, survival and induction.

References 1 Lowes MA, Bowcock AM, Krueger JG: Patho-genesis and therapy of psoriasis. Nature 2007; 445: 886–873.

2 Salgo R, Thaçi D: Treatment of moderate-to-severe plaque psoriasis. G Ital Dermatol Ve-nereol 2009; 144: 701–711.

3 Monteleone G, Pallone F, MacDonald TT, et al: Psoriasis: from pathogenesis to novel ther-apeutic approaches. Clin Sci (Lond) 2010; 120: 1–11.

Dow

nloa

ded

by:

Uni

vers

ity o

f Hon

g K

ong

14

7.8.

31.4

3 -

9/21

/201

3 1:

28:4

0 P

M


10

4 Mattozzi C, Richetta AG, Cantisani C, et al: Psoriasis: new insight about pathogenesis, role of barrier organ integrity, NLR / CATER-PILLER family genes and microbial flora. J Dermatol 2012; 39: 752–760.

5 Gaspari AA: Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol 2006; 54:S67–S80.

6 Gisondi P, Girolomoni G: Biologic therapy in psoriasis: a new therapeutic approach. Auto-immun Rev 2007; 6: 515–519.

7 Lima HC, Kimball AB: Targeting IL-23: in-sights into the pathogenesis and the treatment of psoriasis. Indian J Dermatol 2010; 55: 171–175.

8 Buckner JH: Mechanisms of impaired regula-tion by CD4(+)CD25(+)FOXP3(+) regulato-ry T cells in human autoimmune diseases. Nat Rev Immunol 2010; 10: 849–859.

9 Ochs HD, Gambineri E, Torgerson TR: IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res 2007; 38: 112–121.

10 Brunkow ME, Jeffery EW, Hjerrild KA, et al: Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lympho-proliferative disorder of the scurfy mouse. Nat Genet 2001; 27: 68–73.

11 Sakaguchi S, Ono M, Setoguchi R, et al: Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoim-mune disease. Immunol Rev 2006; 212: 8–27.

12 Zhou X, Bailey-Bucktrout S, Jeker LT, Blue-stone JA: Plasticity of CD4(+) FoxP3(+) T cells. Curr Opin Immunol 2009; 21: 281–285.

13 Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S: Heteroge-neity of natural Foxp3+T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009; 106: 1903–1908.

14 Curotto de Lafaille MA, Lafaille JJ: Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009; 30: 626–635.

15 Horwitz DA, Zheng SG, Gray JD: Naturaland TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror im-ages of each other. Trends Immunol 2008; 29: 429–435.

16 Lim, HW, Broxmeyer HE, Kim CH: Regula-tion of trafficking receptor expression in hu-man forkhead box P3+ regulatory T cells. J Immunol 2006; 177: 840–851.

17 Hoffmann P, Eder R, Boeld TJ, et al: Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 2006; 108: 4260–4267.

18 Zheng SG, Wang J, Wang P, et al: IL-2 isessential for TGF-beta to convert naïve CD4+CD25– cells to CD25+Foxp3+ regula-tory T cells and for expansion of these cells. J Immunol 2007; 178: 2018–2027.

19 Selvaraj RK, Geiger TL: A kinetic and dynam-ic analysis of Foxp3 induced in T cells by TGF-beta. J Immunol 2007; 179:1390ff.

20 Fontenot JD, Rasmussen JP, Gavin MA, et al: A function for interleukin 2 in Foxp3-ex-pressing regulatory T cells. Nat Immunol 2005; 6: 1142–1151.

21 Joetham A, et al: Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induc-tion of TGF-beta. J Immunol 2007; 178: 1433–1442.

22 Shalev I, Wong KM, Foerster K, Zhu Y, Chan C, Maknojia A, Zhang J, Levy G: The novel CD4+CD25+ regulatory T-cell effector mol-ecule fibrinogen-like protein-2 contributes to the outcome of murine fulminant viral hepa-titis. Hepatology 2009; 49: 387–397.

23 Grossman WJ, et al: Differential expression of granzymes A and B in human cytotoxic lym-phocyte subsets and T regulatory cells. Blood 2004; 104: 2840–2848.

24 Deaglio S, et al: Adenosine generation cata-lyzed by CD39 and CD73 expressed on regu-latory T cells mediates immune suppression. J Exp Med 2007; 204: 1257–65.

25 Garin MI, Chu CC, Golshayan D, et al: Galec-tin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 2007; 109: 2058–2065.

26 Read S, Malstrom V, Powrie F: Cytotoxic T lymphocyte associated antigen-4 plays an es-sential role in the function of CD25+CD4+ regulatory cells that control intestinal inflam-mation. J Exp Med 2000; 192: 295–302.

27 Workman CJ, Vignali DAA: Negative regula-tion of T cell homeostasis by LAG-3 (CD223). J Immunol 2004; 174: 688–695.

28 Sarris M, Andersen KG, Randow F, et al: Neu-ropilin-1 expression on regulatory T cells en-hances their interactions with dendritic cells during antigen recognition. Immunity 2008; 28: 402–413.

29 Pandiyan P, Zheng L, Ishihara S, et al: CD4+CD25+FOXP3+ regulatory T cells in-duce cytokine deprivation-mediated apopto-sis of effector CD4+ T cells. Nat Immunol 2007; 8: 1353–1362.

30 Shevach EM: Mechanisms of FOXP3+ T reg-ulatory cell-mediated suppression. Immunity 2009; 30: 636–645.

31 Lim HW, Broxmeyer HE, Kim CH: Regula-tion of trafficking receptor expression in hu-man forkhead box P3+ regulatory T cells. J Immunol 2006; 177: 840–851.

32 Fujio K, Okamura T, Yamamoto K: The fam-ily of IL-10-secreting CD4+ T cells. Adv Im-munol 2010; 105: 99–129.

33 Roncarolo MG, Gregori S, Battaglia M, Bac-chetta R, Fleischhauer K, Levings MK: Inter-leukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006; 212: 28–50.

34 Beissert S, Schwartz A, Schwartz T: Regula-tory T cells. J Invest Dermatol 2006; 126: 15–24.

35 Wan YY, Flavell RA: ‘Yin-yang’ functions of transforming growth factor-β and T regula-tory cells in immune regulation. Immunol Rev 2007; 220: 199–213.

36 Korn T, Bettelli E, Oukka M, et al: IL-17 and TH 17 cells. Annu Rev Immunol 2009; 27: 485–517.

37 Peterson RA: Regulatory T-cells: diverse phe-notypes integral to immune homeostasis and suppression. Toxicol Pathol 2012; 40: 186–204.

38 Sakaguchi S, Yamaguchi T, Nomura T, et al: Regulatory T cells and immune tolerance. Cell 2008; 133: 775–787.

39 Lourenco EV, La Cava A: Natural regulatory T cells in autoimmunity. Autoimmunity 2011; 44: 33–42.

40 Ochs HD, Khattri R, Bennett CL, et al: Im-mune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and the Scurfy mutant mouse. Immunol Allergy Clin North Am 2002; 22: 357–368.

41 Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the tran-scription factor Foxp3. Science 2003; 299: 1057–1061.

42 Walker MR, Kasprowicz DJ, Gersuk VH, etal: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25– T cells. J Clin Invest 2003; 112: 1437–1443.

43 Liu W, Putnam AL, Xu-Yu Z, et al: CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006; 203: 1701–1711.

44 Di Ianni M, Del Papa B, Zei T, et al: T regula-tory cell separation for clinical application. Transfus Apher Sci 2012; 47: 213–216.

45 Liston A, Rudensky AY: Thymic develop-ment and peripheral homeostasis of regula-tory T cells. Curr Opin Immunol 2007; 19: 176–185.

46 Darrasse-Jeze G, Deroubaix S, Mouquet H, et al: Feedback control of regulatory T cell ho-meostasis by dendritic cells in vivo. J Exp Med 2009; 206: 1853–1862.

47 Yates J, Rovis F, Mitchell P, et al: The mainte-nance of human CD4+ CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 pre-serve optimal suppressive potency in vitro. Int Immunol 2007; 19: 785–799.

48 Vignali DA, Collison LW, Workman CJ: How regulatory T cells work. Nat Rev Immunol 2008; 8: 523–532.

49 Yang J, Brook MO, Carvalho-Gaspar M, et al: Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci USA 2007; 104: 19954–19959.

50 Takeda I, Ine S, Killeen N, et al: Distinct roles for the OX40–OX40 ligand interaction in reg-ulatory and nonregulatory T cells. J Immunol 2004; 172: 3580–3589.

51 Choi BK, Bae JS, Choi EM, et al: 4-1BB-de-pendent inhibition of immunosuppression by activated CD4+CD25+ T cells. J Leukoc Biol 2004; 75: 785–791.

52 Tang Q, Adams JY, Penaranda C, et al: Cen-tral role of defective interleukin-2 production in the triggering of islet autoimmune destruc-tion. Immunity 2008; 28: 687–697.

Dow

nloa

ded

by:

Uni

vers

ity o

f Hon

g K

ong

14

7.8.

31.4

3 -

9/21

/201

3 1:

28:4

0 P

M



11

53 Clough LE, Wang CJ, Schmidt EM, et al: Re-lease from regulatory T cell-mediated sup-pression during the onset of tissue specific au-toimmunity is associated with elevated IL-21. J Immunol 2008; 180: 5393–5401.

54 Tang Q, Henriksen KJ, Bi M, et al: In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004; 199: 1455–1465.

55 Kukreja A, Cost G, Marker J, et al: Multiple immuno-regulatory defects in type-1 diabe-tes. J Clin Invest 2002; 109: 131–140.

56 Putnam AL, Vendrame F, Dotta F, et al: CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun 2005; 24: 55–62.

57 Lindley S, Dayan CM, Bishop A, et al: Defec-tive suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Dia-betes 2005; 54: 92–99.

58 Long SA, Cerosaletti K, Bollyky PL, et al: De-fects in IL-2R signaling contribute to dimin-ished maintenance of FOXP3 expression in CD4+CD25+ regulatory T cells of type 1 dia-betic subjects. Diabetes 2010; 59: 407–415.

59 Willcox A, Richardson SJ, Bone AJ, et al: Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol 2009; 155: 173–181.

60 Schneider A, Rieck M, Sanda S, et al: The ef-fector T cells of diabetic subjects are resistant to regulation via CD4+FOXP3+ regulatory T cells. J Immunol 2008; 181: 7350–7355.

61 Lawson JM, Tremble J, Dayan C, et al: In-creased resistance to CD4+CD25hi regulato-ry T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol 2008; 154: 353–359.

62 Kohm AP, Carpentier PA, Anger HA, et al: Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive im-mune responses and central nervous system inflammation during active experimentalautoimmune encephalomyelitis. J Immunol 2002; 169: 4712–4716.

63 Viglietta V, Baecher-Allan C, Weiner HL,et al: Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004; 199: 971–979.

64 Putheti P, Pettersson A, Soderstrom M, et al: Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaf-fected by disease-modulating drugs. J Clin Immunol 2004; 24: 155–161.

65 Feger U, Luther C, Poeschel S, et al: Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immu-nol 2007; 147: 412–418.

66 Kumar M, Putzki N, Limmroth V, et al: CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced prolif-eration in patients with multiple sclerosis. J Neuroimmunol 2006; 180: 178–184.

67 De Andrés C, Aristimuño C, de Las Heras V, et al: Interferon β-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remit-ting multiple sclerosis. J Neuroimmunol 2007; 182: 204–211.

68 Venken K, Hellings N, Thewissen M, et al: Compromised CD4+ CD25high regulatory T-cell function in patients with relapsing-re-mitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology 2007; 123: 79–89.

69 Haas J, Fritzsching B, Trübswetter P, et al: Prevalence of newly generated naive regula-tory T cells (T reg ) is critical for T reg suppres-sive function and determines T reg dysfunction in multiple sclerosis. J Immunol 2007; 179: 1322–1330.

70 Borsellino G, Kleinewietfeld M, Di Mitri D, et al: Expression of ectonucleotidase CD39 by Foxp3+ T reg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007; 110: 1225–1232.

71 Michel L, Berthelot L, Pettré S, et al: Patients with relapsing-remitting multiple sclerosis have normal T reg function when cells express-ing IL-7 receptor α-chain are excluded from the analysis. J Clin Invest 2008; 118: 3411–3419.

72 Haas J, Hug A, Viehöver A, et al: Reduced suppressive effect of CD4+CD25high regula-tory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Im-munol 2005; 35: 3343–3352.

73 Astier AL, Meiffren G, Freeman S, et al: Al-terations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. J Clin Invest 2006; 116: 3252–3257.

74 Gerli R, Nocentini G, Alunno A, et al: Identi-fication of regulatory T cells in systemic lupus erythematosus. Autoimmun Rev 2009; 8: 426–430.

75 Crispin JC, Martinez A, Alcocer-Varela J: Quantification of regulatory T cells in pa-tients with systemic lupus erythematosus. J Autoimmun 2003; 21: 273–276.

76 Miyara M, Amoura Z, Parizot C, et al: Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 2005; 175: 8392–8400.

77 Suen JL, Li HT, Jong YJ, et al: Altered homeo-stasis of CD4+ FoxP3+ regulatory T-cell sub-populations in systemic lupus erythematosus. Immunology 2009; 127: 196–205.

78 Valencia X, Yarboro C, Illei G, et al: Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythema-tosus. J Immunol 2007; 178: 2579–2588.

79 Yan B, Ye S, Chen G, et al: Dysfunctional CD4+, CD25+ regulatory T cells in untreated active systemic lupus erythematosus second-ary to interferon-α-producing antigen-pre-senting cells. Arthritis Rheum 2008; 58: 801–812.

80 Yates J, Whittington A, Mitchell P, et al: Nat-ural regulatory T cells: number and function are normal in the majority of patients with lu-pus nephritis. Clin Exp Immunol 2008; 153: 44–55.

81 Venigalla RK, Tretter T, Krienke S, et al: Re-duced CD4+, CD25 − T cell sensitivity to the suppressive function of CD4+, CD25high, CD127 − /low regulatory T cells in patients with active systemic lupus erythematosus. Ar-thritis Rheum 2008; 58: 2120–2130.

82 Vargas-Rojas MI, Crispín JC, Richaud-Patin Y, et al: Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell re-sistance. Lupus 2008; 17: 289–294.

83 Cao D, Malmström V, Baecher-Allan C, et al: Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid ar-thritis. Eur J Immunol 2003; 33: 215–223.

84 Mottonen M, Heikkinen J, Mustonen L, et al: CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 2005; 140: 360–367.

85 Lawson CA, Brown AK, Bejarano V, et al: Ear-ly rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheuma-tology 2006; 45: 1210–1217.

86 Ehrenstein MR, Evans JG, Singh A, et al: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med 2004; 200: 277–285.

87 Flores-Borja F, Jury EC, Mauri C, et al: De-fects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid ar-thritis. Proc Natl Acad Sci USA 2008; 105: 19396–19401.

88 Saruta M, Yu QT, Fleshner PR, et al: Charac-terization of FOXP3+CD4+ regulatory T cells in Crohn’s disease. Clin Immunol 2007; 125: 281–290.

89 Takahashi M, Nakamura K, Honda K, et al: An inverse correlation of human peripheral blood regulatory T cell frequency with the dis-ease activity of ulcerative colitis. Dig Dis Sci 2006; 51: 677–686.

90 Maul J, Mabarrack N, Barbour A, et al: Pe-ripheral and intestinal regulatory CD4+ CD-25high T cells in inflammatory bowel disease. Gastroenterology 2005; 128: 1868–1878.

91 Li Z, Arijs I, De Hertogh G, et al: Reciprocal changes of Foxp3 expression in blood and in-testinal mucosa in IBD patients responding to infliximab. Inflamm Bowel Dis 2010; 16: 1299–1310.

92 Eastaff-Leung N, Mabarrack N, Barbour A, et al: Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflamma-tory bowel disease. J Clin Immunol 2010; 30: 80–89.

Dow

nloa

ded

by:

Uni

vers

ity o

f Hon

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ong

14

7.8.

31.4

3 -

9/21

/201

3 1:

28:4

0 P

M


12

93 Kelsen J, Agnholt J, Hoffmann HJ, et al: FoxP3+CD4+CD25+ T cells with regulatory properties can be cultured from colonic mu-cosa of patients with Crohn’s disease. Clin Exp Immunol 2005; 141: 549–557.

94 Makita S, Kanai T, Nemoto Y, et al: Intesti-nal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of in-testinal inflammation. J Immunol 2007; 178: 4937–4946.

95 Fantini MC, Rizzo A, Fina D, et al: Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology 2009; 136: 1308–1316.

96 Quaglino P, Antiga E, Comessatti A, et al: Circulating CD4+ CD25brightFOXP3+ reg-ulatory T-cells are significantly reduced in bullous pemphigoid patients. Arch Derma-tol Res 2012; 304: 639–645.

97 Antiga E, Quaglino P, Bellandi S, et al: Regu-latory T cells in the skin lesions and blood of patients with systemic sclerosis and mor-phoea. Br J Dermatol 2010; 162: 1056–1063.

98 Banica L, Besliu A, Pistol G, et al: Quantifica-tion and molecular characterization of regu-latory T cells in connective tissue diseases. Autoimmunity 2009; 42: 41–49.

99 Antiga E, Kretz CC, Klembt R: Characteriza-tion of regulatory T cells in patients with dermatomyositis. J Autoimmun 2010; 35: 342–350.

100 Sather BD, Treuting P, Perdue N, et al: Alter-ing the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflamma-tory disease. J Exp Med 2007; 204: 1335–1347.

101 Hirahara K, Liu L, Clark RA, et al: Themajority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J Immunol 2006; 177: 4488–4494.

102 Kagami S, Rizzo HL, Lee JJ, et al: Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010; 130: 1373–1383.

103 Zhang L, Yang XQ, Cheng J, et al: Increased Th17 cells are accompanied by FoxP3(+) T reg cell accumulation and correlated with psoriasis disease severity. Clin Immunol 2010; 135: 108–117.

104 Zhang K, Li X, Yin G, et al: Functional char-acterization of CD4+CD25+ regulatory T cells differentiated in vitro from bone mar-row-derived haematopoietic cells of psoria-sis patients with a family history of the dis-order. Br J Dermatol 2008; 158: 298–305.

105 Shehata IH, Elghandour TM: A possible pathogenic role of CD4+ CD25+ T-regula-tory cells in psoriasis . Egypt J Immunol 2007; 14: 21–31.

106 Bovenschen HJ, van Vlijmen-Willems IM, van de Kerkhof PC, et al: Identification of lesional CD4+ CD25+ Foxp3+ regulatory T cells in psoriasis. Dermatology 2006; 213: 111–117.

107 Fujimura T, Okuyama R, Ito Y, Aiba S: Pro-files of Foxp3+ regulatory T cells in eczema-tous dermatitis, psoriasis vulgaris and myco-sis fungoides. Br J Dermatol 2008; 158: 1256–1263.

108 Yan KX, Fang X, Han L, et al: Foxp3+ regula-tory T cells and related cytokines differen-tially expressed in plaque vs guttate psoriasis vulgaris. Br J Dermatol 2010; 163: 48–56.

109 Chen L, Shen Z, Wang G, et al: Dynamic fre-quency of CD4+CD25+Foxp3+ T reg cells in psoriasis vulgaris. J Dermatol Sci 2008; 51: 200–203.

110 Richetta AG, Mattozzi C, Salvi M, et al: CD4+ CD25+ T-regulatory cells in psoriasis. Correlation between their numbers and bio-logics-induced clinical improvement. Eur J Dermatol 2011; 21: 344–348.

111 Quaglino P, Ortoncelli M, Comessatti A, et al: Circulating CD4+CD25brightFOXP3+ T cells are up-regulated by biological therapies and correlate with the clinical response in psoriasis patients. Dermatology 2009; 219: 250–258.

112 Diluvio L, Romiti ML, Angelini F, et al: In-fliximab therapy induces increased poly-clonality of CD4+CD25+ regulatory T cells in psoriasis. Br J Dermatol 2010; 162: 895–897.

113 Quaglino P, Bergallo M, Ponti R, et al: Th1, Th2, Th17 and regulatory T cell pattern in psoriatic patients: modulation of cytokines and gene targets induced by etanercept treatment and correlation with clinical re-sponse. Dermatology 2011; 223: 57–67.

114 Richetta AG, Mattozzi C, Salvi M, et al: Downregulation of circulating CD4(+) CD25(bright) Foxp3(+) T cells by cyclospo-rine therapy and correlation with clinical re-sponse in psoriasis patients: report of three cases. Int J Dermatol, E-pub ahead of print.

115 Hess AD, Colombani PM, Esa AH: Cyclo-sporine and the immune response: basic as-pects. Crit Rev Immunol 1986; 6: 123–149.

116 Shintani Y, Yasuda Y, Kobayashi K, et al: Narrowband ultraviolet B radiation sup-presses contact hypersensitivity. Photoder-matol Photoimmunol Photomed 2008; 24: 32–37.

117 Saito C, Maeda A, Morita A: Bath-PUVA therapy induces circulating regulatory T cells in patients with psoriasis. J Dermatol Sci 2009; 53: 231–233.

118 Sugiyama H, Gyulai R, Toichi E, et al:Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoria-sis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Im-munol 2005; 174: 164–173.

119 Goodman WA, Levine AD, Massari JV, et al: IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 2009; 183: 3170–3176.

120 Pasare C, Medzhitov R: Toll pathway-de-pendent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Sci-ence 2003; 299: 1033–1036.

121 Yang XO, Nurieva R, Martinez GJ, et al: Mo-lecular antagonism and plasticity of regula-tory and inflammatory T cell programs. Im-munity 2008; 29: 44–56.

122 Bovenschen HJ, van de Kerkhof PC, van Erp PE, et al: Foxp3+ regulatory T cells of pso-riasis patients easily differentiate into IL-17A-producing cells and are found inlesional skin. J Invest Dermatol 2011; 131: 1853–1860.

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importance of regulatory t cells in the pathogenesis of psoriasis: review of the literature

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