On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.81 no.3 Rio de Janeiro June 2006
Role of regulatory T cells in the development of skin diseases*
Hermênio Cavalcante LimaI
IDermatologist, Allergist and Clinical Immunologist; PhD in Immunology, Adjunct Professor of Clinical Immunology and Allergy, Department of Pathology; Physician and member of the Service of Dermatology and Research Nucleus in Immunodermatology and Clinical Immunology at the Universidade Federal do Paraná - UFPR - Curitiba (PR), Brazil
T cells, particularly CD4+ T cells, have been associated with many aspects of skin disease. Current evidence suggests, however, that the role of CD4+ T lymphocytes in the development of cutaneous inflammation surpasses that of pro-inflammatory activation of effector T cells that direct the immune response. T cell subtypes with regulatory capacity, such as CD4+CD25+high Tregs, have been identified. Recent observations suggest that in some skin diseases the function of these cells is modified. Therefore, the development and function of Treg cells in Dermatology are currently attractive topics because of their importance in controlling the immune system response against tumors and infectious diseases, as well as in inhibiting auto-immunity and allergy development. Therefore, defective regulatory mechanisms may allow a breach in peripheral immune tolerance followed by chronic inflammation and disease. Functional abnormalities and contributions of different subtypes of regulatory T cells in the development of dermatological illnesses are detailed in this review. Possible targets for therapy and modifications of regulatory T cells caused by immunomodulators used in Dermatology are highlighted.
Keywords: Dermatology; Skin diseases; T-Lymphocytes; T-Lymphocytes, suppressor-inducer; Therapeutics
In no other part of the body are inflammatory reactions more apparent than the skin.1 Inflammation may be beneficial, as in defense against tumors or infections, or deleterious, as in dermatitis and psoriasis. Some of these diseases have seen their prevalence double over the last 10 or 15 years since they affect many people worldwide.2,3
The skin is an immunological organ that has antigens for T cells and produces many types of cytokines and inflammatory mediators.4,5 The complex relationships between cells and inflammatory mediators in skin diseases are starting to be unveiled. Several diseases are defined by the production of antibodies and lymphocytes against infectious and environmental antigens.6,7 Additionally, some may result from the triggering of an immune response against auto-antigens of the epidermis or dermis.8
Today, any dermatologist opening a scientific journal on Immunology or Dermatology will observe that suppressor T cells, renamed regulatory T cells Tregs, have become a central concept in immunological vocabulary.9 Regulatory T cells participate in the prevention of autoimmune diseases and other dermatoses.
Hundreds of publications on Tregs have validated the existence of this single line of T cells. The CD4+CD25+highFoxp3+ Treg subpopulation is developed in the thymus and may be peripherally induced during the course of a normal immune response. A repertoire of T cells predisposed against autoantigens is used,10 yet controversy remains over the mechanism of action. in vivo analyses support the model in which Tregs directly or indirectly modify activation and differentiation of pathogenic T cells by means of an effect on antigen-presenting cells.11
The biology and suppression mechanism of these cells are discussed in this review, as well as the manner by which Tregs prevent sensitization and how this regulation process becomes defective or is overcome in individuals with skin disease. Other aspects are mentioned, including immunomodulating therapy that induces inhibitory signals using Tregs. Additionally, we will address the potential for manipulation of Tregs for therapeutical purposes as an attractive form of treatment for many skin diseases. The comprehension of the beneficial mechanisms of these treatments may contain important lessons for immunoregulation of skin diseases.
To conduct a literature review on the role of regulatory T cells associated with the development of skin disease.
Criteria for consideration of studies for this review
All studies, including reviews, clinical trials, editorials, letters, meta-analyses, practical guides, randomized clinical trials and controlled clinical trials published up to January 2006. There was no restriction as to study language.
Research strategy for study identification
Relevant studies were identified in the following electronic databases:
a) MEDLINE (since 1966)
b) Ovid OLDMEDLINE(R) 1950 to 1965
c) EMBASE (as of 1980) and CINAHL (since 1982)
d) Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations
e) LILACS (Latin American and Caribbean Health Science Information)
g) Science Citation Index Expanded (SCI-EXPANDED) 1945-present
h) Social Sciences Citation Index (SSCI) 1956-present
i) Arts & Humanities Citation Index (A&HCI) 1975-present
j) Books@Ovid January 11, 2006
The references of the selected studies were analyzed. Non-published or ongoing studies were researched via correspondence with specialists in the field, authors of relevant projects, and pharmaceutical companies. Summaries of congresses were researched manually.
The search strategy
1. Regulatory T cell OR T-Lymphocytes, Regulatory OR Suppressor Cells OR CD4+CD25+ OR CD25+ Treg Cells OR Th3 Cells OR Tr1 Cells;
2. Skin OR derm* OR cutan* OR Skin disease OR Dermatosis OR Dermatoses;
3. Immunosuppressants OR Immunosuppressive Agents OR Immunomodulators OR Biological Response Modifiers;
These were combined with the search strategy in order to locate articles.
Study selection method
Titles and summaries identified in the investigation were analyzed by the author. Possibly relevant texts were obtained for evaluation. The author decided which publications satisfied the inclusion criteria and quality methodology.
Potential conflict of interest
The author involved in this review performed this appraisal without any known conflict of interest.
REGULATORY T CELLS
Development of an immunological concept
Regulatory T cells
Biological systems are subject to complex regulatory controls and the immune system is no exception. We know that the immune system has the potential to generate lymphocytes against auto-antigens. Experiments, however, suggest that individuals cannot easily be immunized against their own tissues.12 Therefore, a suppression mechanism is necessary to control potentially pathogenic immune cells. Owen suggested that this tolerance against one's own tissues is acquired during the development of the immune system,13 and Burnet proposed that the clonal selective destruction of lymphocytes for auto-antigens occurs primarily in the thymus.14
The destruction of auto-reactive lymphocytes is the primary mechanism that leads to tolerance, but we know that this system is not perfect. B and T lymphocytes can be isolated from normal individuals.15,16 Nishizuka and Sakakura proposed another mechanism for controlling auto-reactive cells. They observed that mice thymectomized between the second and fourth days of life developed an organ-specific autoimmune disease.17 This aggression can be prevented by restoring T cells from the adult thymus or spleen of genetically identical individuals.18 The generation of regulator T cells was proposed in order to explain this mechanism of auto-tolerance attributed to the thymus.19
Other studies observed that the prevention of autoimmune diseases was diminished by the reduction of CD4+ T cells, but not of CD8+ T cells, indicating that regulatory cells belonged to the CD4+ T cell class of lymphocytes.20 Sakaguchi subsequently characterized these regulatory cells as natural CD4+CD25+ Tregs that express Foxp3.21,22
Suppressor T cells
Another control point of the immune response is established when the normal immune response is initiated. A different mechanism must be set off in order to control the magnitude of the response and its termination. This regulation should contribute to limiting clonal expansion and effector cell activity. Soon after the discovery that T lymphocytes function as helper cells for B-lymphocytes, RK Gershon proposed that they could also act as cells capable of suppressing the immune response.23 This subpopulation of suppressor T cells was considered a controller of both auto-reactive and effector cells. A suppressor cell was functionally defined as a lymphocyte that inhibits the immune response by influencing the activity of another type of cell involved in a cascade of suppression factors, a network of anti-idiotypic T cells, and counter-suppressive cells.24
Many of the experiments carried out contain data that support the existence of suppressor T cells. However, the mechanism responsible for these suppressive phenomena was never clearly characterized, and consequently interest in the field of suppressor T cells has gradually dwindled.25 The discovery of Th1/Th2 cells led researchers to abandon the concept of suppressor T cells. Therefore, suppression was the result of counter-regulatory cytokines.26 As pointed out by Green and Webb, the letter ‘‘S'' started to resemble a foul word in cellular immunology, and its use was considered synonymous of scarce data with excessive interpretation or a mystic phenomenon.27
Regulatory T cells are suppressor T cells
Suppressor T cells reappeared as regulatory T cells (Tregs) in the late 1990s when several subpopulations of T cells were identified as having the capacity to inhibit the proliferation of other cells.28 Shevach et al. were the first to call attention to the fact that regulatory T cells and suppressor T cells are the same.29
Therefore, the term ‘regulatory' gradually replaced the term ‘suppressor'. The main problem, however, is not that cells are called regulatory when they should be called suppressors, but that they are considered suppressors. We should understand that regulatory T cells are, in fact, immune response directors instead of its suppressors.30
Phenotype of the regulatory T cell
Tregs are produced in the thymus and are found in peripheral blood and in secondary lymphoid organs.31 Natural regulatory T cells express CD25 constitutionally. The a chain of the IL-2 receptor, CD25, is a marker of T cell activation. However, most activated T cells express CD25 with low to moderate intensity (CD25+int; int = intermediate). Only 1% to 3% of them express CD25 with a high intensity (CD25+high).32 The CD25+high population functions as a regulator.33
In the blood, CD25+high Tregs express the intracellular cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Additionally, they present a phenotype of memory cells since they are CD45RO+, CD45RBlow, besides CD62L and CD38 with a low intensity.34-36 Other markers have been identified as well, such as PD1 or members of the super family of tumor necrosis factor receptors TNFR, such as the glucocorticoid-induced TNFR-related protein - GITR.37
Further studies have revealed that the Foxp3 gene (forkhead box p3) seems to be vital in the development and function of CD25+high Tregs.38 FOXP3, the human analogue of murine Foxp3, was found as a mutation in patients affected by immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (Ipex). In contrast to the other markers of CD25+high Treg, Foxp3 is not induced in the T cells after stimulation.39 Foxp3 is necessary for the development of CD25+high Tregs.40 Foxp3 plays a vital role in the generation of CD25+high Tregs and is the most specific marker available (Figure 1).
Regulation mechanisms of the immune system
The regulation mechanism of the immune system by CD25+high Tregs is not well understood. Studies have not yet arrived at a simple mode of action. Most studies concluded that CD25+high Treg cells suppress by means of a mechanism dependent on cell-to-cell contact,41 The involvement of a molecule tied to the surface was proposed. Such a molecule has not yet been identified, although CTLA-4 is a candidate.43 Suppression requires activation of regulatory T cells by their receptor (TCR) or CD3. However, the presence of antigen-presenting cells (APC) is not required for suppression to occur in vitro.
The in vivo involvement of cytokines was proposed. CD25+high Treg cells are capable of producing IL-10.44 Production of IL-10 by regulatory T cells is necessary for the suppression of certain forms of autoimmune intestinal inflammation.45 Another mechanism that depends on cell-to-cell contact is suppression by the transforming growth factor-b (TGF-b).46 As to the involvement of TGF-b in suppression by these cells, it has become evident that the suppression of CD8+ T cells that induce auto-immunity of tumor rejection requires a TGF-b receptor in the CD8+ T cell.47,48 Therefore, inhibition of CD8+ T lymphocytes needs TGF-b.
A third mechanism of action was proposed by the combination of the other mechanisms. Two independent papers showed that human regulatory cells are capable of inducing, by contact, suppressive properties in CD4+CD25- T cells when they are cultivated in vitro.42 This infectious tolerance was initiated after CD4+CD25+high Tregs began to produce TGF-b49 or IL-10.50
Outras células reguladoras
Several other types of regulatory T cells, such as the gd, T cell, the NKT cell, and CD8+ T cells were described.51 Regulatory CD4+ T cells can be divided into the induced type that secret interleukin-10 (IL-10) and TGF-b, such as TR1 cells,46 and auxiliary T cells (T-helper 3, Th3).52 Naturally occurring cells known as CD4+CD25+high Tregs are the focus of this review (Chart 1).
REGULATORY T CELLS AND SKIN DISEASES
Regulatory homeostatic balance
The homeostatic balance of the immune system is obtained by healthy cellular and humoral responses. Some inflammatory agents, whether physical, chemical, or infectious, induce an intense immune response. This immune response against them frequently results in tissue damage that could be more intense if it were not for the interference of regulatory mechanisms (Figure 2). As has already been specified, Treg cells help limit the damage caused by a vigorous immune response. Natural Treg cells may respond to an ample variety of auto-antigens, although there is evidence that they may also respond to antigens expressed by microbes.53 Induced regulatory T cells, such as TR1 or Th3, may develop from CD4+ T cells when exposed to specific conditions.54,55
Similarly, excessive activity of Treg cells may limit the magnitude of the immune response, which may result in failure to control an infection. On the other hand, the absence of the T regulator may result in intense inflammation and autoimmune dermatitis. Tissue damage may also result from the development of effector cells against their own auto-antigens (Figure 3).
This review discusses the action exerted by regulatory T cells, especially CD4+CD25+high Tregs on skin diseases. In most cases, these diseases are chronic. The various types of influence of these cells suggest that they may act by suppressing or augmenting immunity. The control of Treg cells may affect the results favorably or may be deleterious. However, other factors, such as the immune status and genotype, and the presence of concomitant diseases or other infections may also have an influence. This part of the review also discusses how the manipulation of this balance can be therapeutically explored.
Contact dermatitis is one of the first human diseases in which the role of the T regulator was demonstrated. Results indicate that CD8+ T cells specific for nickel (Ni) are directly related to the expression of contact dermatitis by nickel, while CD4+ T cells specific for Ni may have a regulatory function, possibly via release of IL-10.56 It seems that clones of nickel-specific CD4+ T cells in non-allergic individuals exhibit a low production of IFN-g and an increased production of IL-10 in comparison to clones of allergic patients. These Ni-reactive IL-10high CD4+ T cell clones remind us of a TR1 subpopulation.57 New studies show that other haptens that are inducers of delayed-type hypersensitivity also induce a migration of regulatory T cells to inflamed skin.58 In this case, the CD8+ T cells are also effector cells, and CD4+CD25+high cells are regulators.59
CD4+ effector cells in the presence of Ni, and TR1 cells reactive to Ni or treated with extracts of TR1 cell cultures exhibited a lowered capacity to stimulate a specific Th1 response to nickel. Therefore, TR1 can regulate the expression of allergic diseases mediated by the Th1 response via the release of IL-10.60 TR1 cells may limit excessive reactions against haptens by blocking the specific Th1 response. The high incidence of TR1 in non-allergic individuals also suggests that these cells can determine if the immune response will be silent or develop further. CD4+CD25+high Treg cells suppress contact hypersensitivity reactions by blocking the influx of effector cells into the inflamed tissue in vivo.61 These aspects identify immunotherapy targets for allergic contact dermatitis.
Th2 cells play a critical role in the pathogenesis of atopic dermatitis. Nonetheless, the immune mechanisms that reduce and protect against the development of this disorder are poorly understood.62 A spectrum of CD4+ T cells, including Th3, TR1 and Treg CD4+CD25+high, and NKT cells seem to participate in the regulation of atopic diseases.63 This may be related to the fact that patients with Ipex develop serious dermatitis, high levels of IgE, and sometimes, eosinophilia.64 Atopic dermatitis can result from an inappropriate balance between CD4+CD25+high Treg cells activated by the allergen and Th2 effector cells. This imbalance may result from a deficiency in suppression by the regulatory T cells or by strong activation signals that supersede the regulatory mechanism.65 As to the first possibility, the increase of regulatory cells confers protection against atopic inflammation.66 However, other authors documented that patients with atopic dermatitis have a CD4+CD25+high Treg population that is not numerically or functionally different from that of normal individuals.67
Psoriasis is sustained by the activation of pathogenic T cells. In psoriasis, the subpopulation of CD4+ T lymphocytes in peripheral blood, phenotypically CD25+high, CTLA-4(+), Foxp3high, is deficient in its suppressor functions.68 This is associated with an accelerated proliferation of the CD4+ T cell response.69 The presence of non-functional CD4+CD25+high Treg cells in peripheral blood and in tissues may lead to a reduced capacity to contain pathogenic T cells and to a hyperproliferation of the psoriatic plaque in vivo.70 These findings represent a critical component of this autoimmune disease and may have implications for potential therapy by manipulation of CD4+CD25+high Tregs in vivo.
CD4+CD25+high Treg cells have inhibitory properties against the development of autoimmune diseases.71 Alopecia areata, a disease that affects the anagen phase of hair follicles, has the participation of CD4+CD25+high Treg cells in the mechanism of the disease. It was noted, for example, that in the draining lymph node and spleen of experimental models affected by the disease, only a few CD4+CD25+high Treg cells were detected even though the number of CD25+ cells was unchanged.72 These data suggest that the status of the disease is maintained by the expression of elevated cytokine levels, an increased number of CD4+ e CD8+, but reduced levels of CD4+CD25+high Treg cells.
Similar observations were encountered in humans; mononucleate cells from peripheral blood of patients with alopecia areata contain an increase of recently activated CD4+CD25+CD154+ T cells resistant to apoptosis, characterized by CD95-. These data indicate a progressive loss of Tregs in patients with alopecia areata.73 However, delayed-type hypersensitivity reactions as a means of treatment for alopecia areata have no impact on T regulators.74 In summary, CD8+ T cells may be the principal inducers of hair loss.75 Nevertheless, the expression of the disease is determined by CD4+CD25+int T cells, while CD4+CD25+high Treg cells have a regulatory role.76
During the experimental infection of mice with Candida albicans, the reduction in CD4+CD25+high Treg cells induces a better control of infection, but it is associated with an increase of the intestinal inflammatory lesion.77 PTherefore, the reduction of natural Treg cells leads to a better primary control of infections by C. albicans. Nevertheless, there is an increase in tissue lesions as well as a loss of immunity against reinfection unless the regulator cells are reconstituted.78 This model shows that a balance dependent on natural Treg cells can be established between the host and the pathogen that benefits both.
The experimental infection model with Leishmania major provided a good example of the fact that natural Treg cells are necessary for pathogen survival. In the L. major infection model without cure, the infection results in progressive lesions caused by the Th2 response.79 It is important to consider the role of IL-10 produced by natural CD4+CD25+high Treg cells in the susceptibility to L. major, since these cells seem to suppress the capacity of the CD4+ T lymphocytes specific for L. major to produce a sterile cure.80 Hence, the amplitude of the response and the subsequent tissue lesion are controlled by natural Treg cells.81 IL-10 produced by CD4+ T cells is as important as IL-4 in the progression of susceptibility to infections by L. major. This observation raises the issue as to whether these cytokines are secreted by the same Th2 cells or produced by a discrete subpopulation of CD4+ T cells that arises from different cell clones activated by other antigens.82
Ultraviolet radiation (UV)
A reduction in immune response induced by UV was observed in several models. For example, it was demonstrated that the application of an allergen to skin exposed to UV does not result in sensitization, but in tolerance to the hapten.83 This tolerance can be transferred to animals not previously sensitized.84 The T regulator responsible for this type of tolerance belongs to the CD4+CD25+high subtype.85
DNA damage is considered the greatest molecular inducer of UV-induced immunosuppression. Migration of dendritic cells containing damaged DNA seems to set off the production of Tregs in the lymph node.86 Based on these data, it is possible to consider that these cells perform a role in photocarcinogenesis. Participation of the T suppressor in tumors induced by UV has been described since 1982.87 However, it was only recently that these cells were characterized as natural killer T suppressor cells (NKT).88
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. As is true in other related entities, its etiology is unknown. Multiple defects in the immune systems of patients with this condition have been described. The involvement of regulator T cells in this disease is under study. Patients with active SLE exhibit a quantitative defect of natural CD4+CD25+high Treg cells. A decrease in natural CD4+CD25+high Treg cells correlates with the clinical seriousness of the skin lesions.89 This defect is absent during the remission of the disease. Relapses of SLE are therefore associated with the global decline of these cells and do not represent some phenomenon of tissue redistribution.90
Another example of the connection between the T regulator and a pathogen has been observed in infections with the herpes simplex virus (HSV). Treg cells protect the tissue of the lesion mediated by CD4+ T lymphocytes when it is submitted to a low intensity viral infection, a situation compatible with the establishment of immunity against reinfection. Natural CD4+CD25+high Treg cells suppress virus-specific CD8+ T cells and retard viral elimination. Actually, non-pathogenic doses of the virus may induce tissue damage in the absence of natural Treg cells.91 A greater resistance to the viral challenge determined by CD4+ e CD8+ T cells was also demonstrated in these animals.92 Regulator T cells isolated from lesions in vitro exhibit an inhibitory effect involving IL-10.93 Natural CD4+CD25+high Treg cells were also encountered among inflammatory cells of sensory ganglions infected by HSV. It is possible that these serve to prevent the destruction of infected neurons in the site by the effector T cells.94 These results suggest that the manipulation of regulatory cell function may be a useful approach for the control of immunoinflammatory diseases induced by the virus.
Regulator T cells seem to also modify the immune response to infection by the Epstein-Barr virus (EBV) in human beings. The EBV infection induces IL-10-secreting Treg cells that are specific for the latent membrane protein 1 (LMP1) of the EBV. These cells inhibit the Th1 response against EBV proteins, which should facilitate viral persistence and promote the induction of tumors associated to the EBV.95
AIDS is associated with the loss of CD4+ T cells and progressive immune dysfunction. Evidence suggests that immunity against infection by the human immunodeficiency virus (HIV) may be controlled by natural Treg cells.96,97 Removal of Treg cells from peripheral blood results in an increase of the anti-HIV CD4+ T response. Paradoxically, depletion of regulator T cells in the HIV infection is associated with immune activation and worsening of the patient's clinical status,98,99 since the response of CD4+ and CD8+ T cells specific against the HIV is diminished by the Treg cells.100 This suppression depends on cell-to-cell contact and does not depend on cytokines, supporting the idea of natural Treg cell involvement.101
At the Universidade Federal do Paraná it was recently demonstrated that Tregs in children infected with HIV might regulate the expression of inflammatory and infectious dermatoses, altering their prevalence in this population according to the immune status of the individual.102 Additionally, in another study of the same population, it was noted that Treg cells can also interfere in the expression of the response to environmental allergens evaluated by the prick test.103
TR1 cells were preferentially isolated from peripheral blood of healthy individuals who carry the genetic tendency for developing pemphigus vulgaris (PV) and from only a minority of patients with PV. The TR1 cells exhibited their inhibitory effect on the proliferation of auto-reactive Th clones responsive to desmoglein 3 (Dsg3). This capacity was not dependent on cell-to-cell contact and was mediated by cytokines IL-10 and TGF-b. These findings suggest that these cells may be involved in the maintenance of auto-tolerance to Dsg3.104 In another study, blocking of the interaction between CD40 and CD154 and the monoclonal antiCD154 (antiCD154 mAb) antibody reduced the production of IgG antiDsg3 and prevented the formation of lesions in the experimental model of PV. The resulting tolerance to Dsg3 was transferred by the splenic cells of animals treated with anti-CD154 mAb. These data suggest that anti-CD154 mAb induced tolerance to Dsg3 by the induction of immunoregulator cells.105 Hence, TR1 cells responsive to Dsg3 or immunoregulator cells induced by treatment with anti-CD154 may represent an ideal tool for therapeutically restoring Dsg3-specific immune tolerance.
CLINICAL AND THERAPEUTICAL CONSEQUENCES OF T REGULATORS
Today, regulator T cells are now better known.106 They were isolated from human beings and animals.25 An improved understanding of the role of T regulators in skin diseases may lead to the identification of new targets for treatment. More specifically, the goal is to manipulate natural regulator cells or those induced by means of an increase or decrease of their function, depending on the circumstances.
Tolerance depends on natural CD4+CD25+high Treg cells that arise in young CD25- cells and regulate their effect by means of IL-10 and CTLA-4. The induction of a dominant tolerance in an allograft depends on regulatory T cells and does not necessarily result in an attenuation of the response against pathogens. Thus, there is an interest in the development of tolerance protocols in clinical aspects of transplants.107 Proliferative and cytotoxic events involving T cells, Tregs, and NK have been implicated in the therapeutical effect of bone marrow transplants in treatments for autoimmune diseases.108
In the specific field of dermatology, the stimulation of Treg cells may be important in autoimmune diseases. For example, blockage of T lymphocyte stimulation, as in the use of the antibody associated to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4-immunoglobulin, CTLA4Ig), reverts the development of psoriatic plaques.109
Auto-injections of regulator T cells are a promising approach to modulation of inflammation and autoimmune diseases.110,111 Nevertheless, there is a significant decline in the function of natural CD4+CD25+high Treg cells of peripheral blood in patients with autoimmune diseases when compared to that of healthy individuals.112,113 In order to overcome this difficulty, cytokines were used to stimulate the growth of regulator T cells. IL-15 allows a significant in vitro expansion of regulator cells.114 Natural CD4+CD25+high Treg cells obtained by ex vivo expansion through stimulation with allogeneic antigen-presenting cells and IL-2 were capable of modulating the graft-versus-host disease (GVHD).115
On the other hand, induction of natural CD4+CD25+high Treg cells may facilitate the establishment and maintenance of immunological tolerance. Depletion of natural CD4+CD25+high Treg cells may be an effective way of reversing the tolerance induced by malignant tumors and increasing the activity of the immune system against cancer epitopes.116,117
For now, we should be attentive to the effect of immunomodulator drugs on these cells. For example, tacrolimus, an inhibitor of calcineurin, increases the inhibition of Treg cells in atopic dermatitis.67 Fludarabine reduces the frequency and suppressive function of natural CD4+CD25+high Treg cells.118 Low doses of cyclophosphamide induce the inhibition of natural CD4+CD25+high Treg cells and consequently increase the immune response in an apparently paradoxical effect.119 Along the same line, cyclophosphamide decreases the function, proportion, and number of natural CD4+CD25+high Treg cells that suppress the induction of contact hypersensitivity.120
Currently, corticosteroids constitute the most effective treatment for inflammatory skin diseases. These drugs are effective in inhibiting the function of Th2 cells, eosinophiles, and epithelial cells. However, treatment with these drugs during the presentation of the epitope may result in an increased tolerance by suppressing the development of dendrite cells that secrete IL-10, which are necessary for the induction of T regulators. Therefore, treatment with corticosteroids may increase the subsequent effect of the T response and aggravate, on the long run, the course of inflammatory diseases.121 This aspect may also be related to the rebound effect of inflammatory diseases once these drugs are removed.
Currently, regulatory or suppressor T cells have their existence recognized despite skepticism on the part of most immunologists. They may be isolated from peripheral blood in humans. Other regulatory cells may be induced by the natural progression of the immune response.
Natural CD4+CD25+high Treg cells and other cells seem to play a vital role in maintaining tolerance to endogenous antigens and in regulating the immune response induced by exogenous antigens. In recent years, more research has been done on their involvement in several skin diseases. Treg cells may be altered, qualitatively or quantitatively, in skin diseases in humans, suggesting their role in the pathophysiology of these illnesses. A detailed comprehension of the associations among the various regulator cells may help in understanding the events that lead to the appearance of skin diseases. In due course, a specific way to manipulate the function of regulator T cells according to the desired effect will be the goal.
1. Nordlind K, Vahlquist A. Nya trender inom immundermatologi och hudterapi. Lakartidningen. 1999.24;96:876-81. [ Links ]
2. Ljubojevic S, Lipozencic J, Brenner S, Budimcic D. Pemphigus vulgaris: a review of treatment over a 19-year period. J Eur Acad Dermatol Venereol. 2002;16:599-603. [ Links ]
3. Russell-Jones R, Powell AM, Acland K, Calonje E, O'Doherty M, Healy C. The chances of a patient with melanoma developing in transit disease are doubled by undergoing sentinel lymph node biopsy (SLNB). Eur J Surg Oncol. 2005;31:210-1. [ Links ]
4. Brown DW, Baker BS, Ovigne JM, Hardman C, Powles AV, Fry L. Skin CD4+ T cells produce interferon-gamma in vitro in response to streptococcal antigens in chronic plaque psoriasis. J Invest Dermatol. 2000;114:576-80. [ Links ]
5. Ewida AS, Raphael SA, Abbasi JA, Geslani GP, Bagasra O. Evaluation of Th-1 and Th-2 immune responses in the skin lesions of patients with Blau syndrome. Appl Immunohistochem Mol Morphol. 2002;10:171-7. [ Links ]
6. Hertl M, Riechers R. Analysis of the T cells that are potentially involved in autoantibody production in pemphigus vulgaris. J Dermatol. 1999;26:748-52. [ Links ]
7. Rizzo C, Fotino M, Zhang Y, Chow S, Spizuoco A, Sinha AA. Direct characterization of human T cells in pemphigus vulgaris reveals elevated autoantigen-specific Th2 activity in association with active disease. Clin Exp Dermatol. 2005;30:535-40. [ Links ]
8. Novak N, Bieber T. The skin as a target for allergic diseases. Allergy. 2000;55:103-7. [ Links ]
9. Horwitz DA, Gray JD, Zheng SG. The potential of human regulatory T cells generated ex vivo as a treatment for l0upus and other chronic inflammatory diseases. Arthritis Res. 2002;4:241-6. [ Links ]
10. Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, et al. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med. 2002.15;196:237-46. [ Links ]
11. Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol. 2005;17:638-42. [ Links ]
12. Silverstein AM. Horror Autotoxicus: the concept of autoimmunity. A history of Immunology. San Diego : Academic Press; 1989. p.160-89. [ Links ]
13. Talmage DW. Origins of the cell selection theories of antibody formation. In: Gallagher RB, Gilder J, Nossal GJV, Salvatore G, editors. Immunology: The making of a modern science. London : Academic Press Limited; 1995. p.23-7. [ Links ]
14. Burnet FM. A modification of Jerne's theory of antibody production using the concept of clonal selection. CA Cancer J Clin. 1976;26:119-21. [ Links ]
15. Gay D, Saunders T, Camper S, Weigert M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med. 1993;177:999-1008. [ Links ]
16. Ramsdell F, Fowlkes BJ. Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. Science. 1990.15;248:1342-8. [ Links ]
17. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science. 1969.7;166:753-5. [ Links ]
18. Sakakura T, Nishizuka Y. Thymic control mechanism in ovarian development: reconstitution of ovarian dysgenesis in thymectomized mice by replacement with thymic and other lymphoid tissues. Endocrinology. 1972;90:431-7. [ Links ]
19. Sakaguchi S, Toda M, Asano M, Itoh M, Morse SS, Sakaguchi N. T cell-mediated maintenance of natural self-tolerance: its breakdown as a possible cause of various autoimmune diseases. J Autoimmun. 1996;9:211-20. [ Links ]
20. Han HS, Jun HS, Utsugi T, Yoon JW. A new type of CD4+ suppressor T cell completely prevents spontaneous autoimmune diabetes and recurrent diabetes in syngeneic islet-transplanted NOD mice. J Autoimmun. 1996;9:331-9. [ Links ]
21. Sakaguchi S. The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery. J Clin Invest. 2003;112:1310-2. [ Links ]
22. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001;182:18-32. [ Links ]
23. Gershon RK, Kondo K. Infectious immunological tolerance. Immunology. 1971;21:903-14. [ Links ]
24. Dorf ME, Benacerraf B. Suppressor cells and immunoregulation. Annu Rev Immunol. 1984;2:127-57. [ Links ]
25. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol. 2001;2:816-22. [ Links ]
26. Shevach EM. Regulatory T cells in autoimmmunity*. Annu Rev Immunol. 2000;18:423-49. [ Links ]
27. Green DR, Webb DR. Saying the 'S' word in public. Immunol Today. 1993;14:523-5. [ Links ]
28. Nagler-Anderson C, Bhan AK , Podolsky DK, Terhorst C. Control freaks: immune regulatory cells. Nat Immunol. 2004;5:119-22. [ Links ]
29. Shevach EM, Thornton A, Suri-Payer E. T lymphocyte-mediated control of autoimmunity. Novartis Found Symp. 1998;215:200-11; discussion 211-30. [ Links ]
30. Barthlott T, Kassiotis G, Stockinger B. T cell regulation as a side effect of homeostasis and competition. J Exp Med. 2003;197:451-60. [ Links ]
31. Taams LS, Vukmanovic-Stejic M, Smith J, Dunne PJ, Fletcher JM, Plunkett FJ, et al. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur J Immunol. 2002;32:1621-30. [ Links ]
32. Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E. Characterization of human CD25+ CD4+ T cells inthymus, cord and adult blood. Immunology. 2002;106:190-9. [ Links ]
33. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245-53. [ Links ]
34. Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med. 1996;183:2669-74. [ Links ]
35. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193:1285-94. [ Links ]
36. Lepault F, Gagnerault MC. Characterization of peripheral regulatory CD4+ T cells that prevent diabetes onset in nonobese diabetic mice. J Immunol. 2000;164:240-7. [ Links ]
37. Curotto de Lafaille MA, Lafaille JJ. CD4(+) regulatory T cells in autoimmunity and allergy. Curr Opin Immunol. 2002;14:771-8. [ Links ]
38. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-62. [ Links ]
39. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057-61. [ Links ]
40. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330-6. [ Links ]
41. Ermann J, Szanya V, Ford GS, Paragas V, Fathman CG, Lejon K. CD4(+)CD25(+) T cells facilitate the induction of T cell anergy. J Immunol. 2001;167:4271-5. [ Links ]
42. Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002;2:389-400. [ Links ]
43. Nishimura E, Sakihama T, Setoguchi R, Tanaka K, Sakaguchi S. Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells. Int Immunol. 2004;16:1189-201. [ Links ]
44. Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol. 2001;166:3008-18. [ Links ]
45. Suri-Payer E, Cantor H. Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4(+)CD25(+) T cells. J Autoimmun. 2001;16:115-23. [ Links ]
46. Levings MK, Bacchetta R, Schulz U, Roncarolo MG. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol. 2002;129:263-76. [ Links ]
47. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A. 2005;102:419-24. [ Links ]
48. Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A. 2003;100:10878-83. [ Links ]
49. Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH. Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med. 2002;196:255-60. [ Links ]
50. Dieckmann D, Bruett CH, Ploettner H, Lutz MB , Schuler G. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J Exp Med. 2002;196:247-53. [ Links ]
51. Bach JF. Regulatory T cells under scrutiny. Nat Rev Immunol. 2003;3:189-98. [ Links ]
52. Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev. 2001;182:207-14. [ Links ]
53. Kumar V. Homeostatic control of immunity by TCR peptide-specific Tregs. J Clin Invest. 2004;114:1222-6. [ Links ]
54. Taams LS, Akbar AN. Peripheral generation and function of CD4+CD25+ regulatory T cells. Curr Top Microbiol Immunol. 2005;293:115-31. [ Links ]
55. Foussat A, Cottrez F, Brun V, Fournier N, Breittmayer JP, Groux H. A comparative study between T regulatory type 1 and CD4+CD25+ T cells in the control of inflammation. J Immunol. 2003;171:5018-26. [ Links ]
56. Cavani A, Mei D, Guerra E, Corinti S, Giani M, Pirrotta L, et al. Patients with allergic contact dermatitis to nickel and nonallergic individuals display different nickel-specific T cell responses. Evidence for the presence of effector CD8+ and regulatory CD4+ T cells. J Invest Dermatol. 1998;111:621-8. [ Links ]
57. Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997;389:737-42. [ Links ]
58. Lecart S, Boulay V, Raison-Peyron N, Bousquet J, Meunier L, Yssel H, et al. Phenotypic Characterization of Human CD4+ Regulatory T Cells Obtained from Cutaneous Dinitrochlorobenzene-Induced Delayed Type Hypersensitivity Reactions. J Invest Dermatol. 2001;117:318-25. [ Links ]
59. Hennino A, Vocanson M, Chavagnac C, Saint-Mezard P, Dubois B, Kaiserlian D, et al. Fisiopatologia da dermatite de contato alérgica: papel das células T CD8 efetoras e das células T CD4 regulatórias. An Bras Dermatol. 2005;80:335-47. [ Links ]
60. Cavani A, Nasorri F, Prezzi C, Sebastiani S, Albanesi C, Girolomoni G. Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J Invest Dermatol. 2000;114:295-302. [ Links ]
61. Schafer SC, Ring S, Enk AH, Lehr HA. CD4+CD25+ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue in vivo. J Vasc Res. 2006;43:33. [ Links ]
62. Bellinghausen I, Knop J, Saloga J. The role of regulatory CD4(+) CD25(+) T cells in allergic diseases. Allergologie. 2004;27:444-9. [ Links ]
63. Akbari O, Stock P, DeKruyff RH, Umetsu DT. Role of regulatory T cells in allergy and asthma. Curr Opin Immunol. 2003;15:627-33. [ Links ]
64. Nieves DS, Phipps RP, Pollock SJ, Ochs HD, Zhu Q, Scott GA, et al. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol. 2004;140:466-72. [ Links ]
65. Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet. 2004;363:608-15. [ Links ]
66. Zuany-Amorim C, Sawicka E, Manlius C, Le Moine AL, Brunet LR, Kemeny DM, et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med. 2002;8:625-9. [ Links ]
67. Vukmanovic-Stejic M, McQuaid A, Birch KE, Reed JR, Macgregor C, Rustin MH, et al. Relative impact of CD4+CD25+ regulatory T cells and tacrolimus on inhibition of T-cell proliferation in patients with atopic dermatitis. Br J Dermatol. 2005;153:750-7. [ Links ]
68. Sugiyama H, Gyulai RP, Shimada S, Cooper KD, Stevens SR, McCormick TS. Decreased suppressive capacity of psoriatic CD4+CD25+ regulatory T cells: a novel mechanism for sustained autoreactivity in psoriasis. J Invest Dermatol. 2002;119:299. [ Links ]
69. Garaczi E, Goodman W, Sugiyama H, Gyulai R, McCormick TS, Cooper KD. Identification of a unique population of regulatory T cells in psoriasis by elimination of transiently activated CD4+CD25+cells. J Invest Dermatol. 2004;122:A120-A. [ Links ]
70. Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol. 2005;174:164-73. [ Links ]
71. Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN. Human anergic/suppressive CD4(+) CD25(+) T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol. 2001;31:1122-31. [ Links ]
72. Zoller M, McElwee KJ, Engel P, Hoffmann R. Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata. J Invest Dermatol. 2002;118:983-92. [ Links ]
73. Zoller M, McElwee KJ, Vitacolonna M, Hoffmann R. Apoptosis resistance in peripheral blood lymphocytes of alopecia areata patients. J Autoimmun. 2004;23:241-56. [ Links ]
74. Zoller M, Freyschmidt-Paul P, Vitacolonna M, McElwee KJ, Hummel S, Hoffmann R. Chronic delayed-type hypersensitivity reaction as a means to treat alopecia areata. Clin Exp Immunol. 2004;135:398-408. [ Links ]
75. Rivitti EA. Alopecia areata: revisäo e atualizaçäo. An Bras Dermatol. 2005;80:57-68. [ Links ]
76. McElwee KJ, Freyschmidt-Paul P, Hoffmann R, Kissling S, Hummel S, Vitacolonna M, et al. Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model. J Invest Dermatol. 2005;124:947-57. [ Links ]
77. Montagnoli C, Bacci A, Bozza S, Gaziano R, Mosci P, Sharpe AH, et al. B7/CD28-dependent CD4+CD25+ regulatory T cells are essential components of the memory-protective immunity to Candida albicans. J Immunol. 2002;169:6298-308. [ Links ]
78. Walker LSK. CD4+ CD25+ Treg: divide and rule? Immunology. 2004;111:129-37.
79. Sacks D, Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol. 2002;2:845-58. [ Links ]
80. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature. 2002;420:502-7. [ Links ]
81. Xu D, Liu H, Komai-Koma M, Campbell C, McSharry C, Alexander J, et al. CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J Immunol. 2003;170:394-9. [ Links ]
82. Sacks D, Anderson C. Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice. Immunol Rev. 2004;201:225-38. [ Links ]
83. Toews GB, Bergstresser PR, Streilein JW. Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J Immunol. 1980;124:445-53. [ Links ]
84. Elmets CA, Bergstresser PR, Tigelaar RE, Wood PJ, Streilein JW. Analysis of the mechanism of unresponsiveness produced by haptens painted on skin exposed to low dose ultraviolet radiation. J Exp Med. 1983;158:781-94. [ Links ]
85. Schwarz A, Maeda A, Wild MK, Kernebeck K, Gross N, Aragane Y, et al. Ultraviolet radiation-induced regulatory T cells not only inhibit the induction but can suppress the effector phase of contact hypersensitivity. J Immunol. 2004;172:1036-43. [ Links ]
86. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med. 2000;192:1213-22. [ Links ]
87. Fisher MS, Kripke ML. Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice. Science. 1982;216:1133-4. [ Links ]
88. Moodycliffe AM, Nghiem D, Clydesdale G, Ullrich SE. Immune suppression and skin cancer development: regulation by NKT cells. Nat Immunol. 2000;1:521-5. [ Links ]
89. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun. 2003;21:273-6. [ Links ]
90. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol. 2005;175:8392-400. [ Links ]
91. Suvas S, Azkur AK , Kim BS, Kumaraguru U, Rouse BT. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol. 2004;172:4123-32. [ Links ]
92. Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT. CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med. 2003;198:889-901. [ Links ]
93. Toka FN, Suvas S, Rouse BT. CD4(+) CD25(+) T cells regulate vaccine-generated primary and memory CD8(+) T-cell responses against herpes simplex virus type 1. J Virol. 2004;78:13082-9. [ Links ]
94. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6:353-60. [ Links ]
95. Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood. 2004;103:1755-62. [ Links ]
96. Beilharz MW, Sammels LM, Paun A, Shaw K, van Eeden P, Watson MW, et al. Timed ablation of regulatory CD4(+) T cells can prevent murine AIDS progression. J Immunol. 2004;172:4917-25. [ Links ]
97. Tsunemi S, Iwasaki T, Imado T, Higasa S, Kakishita E, Shirasaka T, et al. Relationship of CD4+CD25+regulatory T cells to immune status in HIV-infected patients. AIDS. 2005;19:879-86. [ Links ]
98. Eggena MP, Barugahare B, Jones N, Okello M, Mutalya S, Kityo C, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol. 2005;174:4407-14. [ Links ]
99. Kinter AL, Hennessey M, Bell A, Kern S, Lin Y, Daucher M, et al. CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med. 2004;200:331-43. [ Links ]
100.Nixon DF, Aandahl EM, Michaelsson J. CD4(+)CD25(+) regulatory T cells in HIV infection. Microbes Infect. 2005;7:1063-5. [ Links ]
101.Suvas S, Rouse BT. Regulation of microbial immunity: the suppressor cell renaissance. Viral Immunol. 2005;18:411-8. [ Links ]
102.de Carvalho VO. Diferenças na prevalência de dermatoses inflamatórias e infecciosas conforme a alteração imunológica do paciente pediátrico infectado pelo HIV [tese]. Curitiba: Universidade Federal do Paraná; 2005. [ Links ]
103.da Cruz RC. Cinética dos marcadores laboratoriais de atopia em crianças infectadas pelo HIV [tese]. Curitiba : Universidade Federal do Paraná; 2005. p.70. [ Links ]
104.Veldman C, Hohne A, Dieckmann D, Schuler G, Hertl M. Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J Immunol. 2004;172:6468-75. [ Links ]
105.Aoki-Ota M, Kinoshita M, Ota T, Tsunoda K, Iwasaki T, Tanaka S, et al. Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model. J Invest Dermatol. 2006;126:105-13. [ Links ]
106.Levings AK, Roncarolo MG. Phenotypic and functional differences between human CD4(+)CD25(+) and type 1 regulatory T cells. In: Kyewski B, Suri-Payer E, editors. Cd4+CD25+ Regulatory T Cells: Origin, Function and Therapeutic Potential. Germany : Springer; 2005. p. 303-26. [ Links ]
107.Bushell A, Jones E, Gallimore A, Wood K. The generation of CD25(+)CD4(+) regulatory T cells that prevent allograft rejection does not compromise immunity to a viral pathogen. J Immunol. 2005;174:3290-7. [ Links ]
108.Voltarelli J, Palma P, Morais F, Castro F. Immunological effects of donor lymphocyte infusion in patients with chronic myelogenous leukemia relapsing after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2004;10:53-4. [ Links ]
109.Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang SW, et al. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J Exp Med. 2000;192:681-93. [ Links ]
110.Takayashiki T, Asakura H, Ku G, Kataoka M, Flye MW. Infectious tolerance develops after intrathymic alloantigen-induced acceptance of rat heart allografts can be adoptively transferred. Surgery. 2005;138:254-60. [ Links ]
111.Loser K, Hansen W, Apelt J, Balkow S, Buer J, Beissert S. In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity. Gene Therapy. 2005;12:1294-304. [ Links ]
112.Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4(+)CD25(+) regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971-9. [ Links ]
113.Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med. 2004;199:1285-91. [ Links ]
114.Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, Roncarolo MG. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol. 2002;32:2237-45. [ Links ]
115.Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med. 2002;196:401-6. [ Links ]
116.Nicholl M, Lodge A, Brown I, Sugg SL. Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells. J Pediatr Surg. 2004;39:941-6. [ Links ]
117.Yu P, Lee Y, Liu WH, Krausz T, Chong A, Schreiber H, et al. Intratumor depletion of CD4(+) cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med. 2005;201:779-91. [ Links ]
118.Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, et al. Reduced frequencies and suppressive function of CD4(+)CD25(hi) regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106:2018-25. [ Links ]
119.Lutsiak MEC, Semnani RT, De Pascalis R, Kashmiri SVS, Schlom J, Sabzevari H. Inhibition of CD4(+)25(+) T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862-8. [ Links ]
120.Ikezawa Y, Nakazawa M, Tamura C, Takahashi K, Minami M, Ikezawa Z. Cyclophosphamide decreases the number, percentage and the function of CD25(+) CD4(+) regulatory T cells, which suppress induction of contact hypersensitivity. J Dermatol Sci. 2005;39:105-12. [ Links ]
121.Stock P, Akbari O, DeKruyff RH, Umetsu DT. Respiratory tolerance is inhibited by the administration of corticosteroids. J Immunol. 2005;175:7380-7. [ Links ]
Correspondence Conflict of interests: None *Work done at Dermatology Service
SAM4, Hospital das Clínicas da Universidade Federal do Paraná
- UFPR - Curitiba (PR), Brazil.
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Conflict of interests: None
*Work done at Dermatology Service SAM4, Hospital das Clínicas da Universidade Federal do Paraná - UFPR - Curitiba (PR), Brazil.