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Regulatory T Cells and Immunodeficiency in Mycosis Fungoides and SÉ

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Regulatory T Cells and Immunodeficiency in Mycosis Fungoides and SÉ Leukemia (2012) 26, 424–432 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu REVIEW Regulatory T cells and immunodeficiency in mycosis fungoides and Se´zary syndrome T Krejsgaard1,2, N Odum1,2, C Geisler1, MA Wasik3 and A Woetmann1,2 1Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; 2Department of Biology, University of Copenhagen, Copenhagen, Denmark and 3Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA Cutaneous T-cell lymphoma (CTCL) is the term for diseases leukemic variant of CTCL with a median survival of 3 years that characterized by primary accumulation of malignant T cells in is characterized by generalized erythroderma, lymphadenopa- the skin. Patients with the two predominant clinical forms of thy and the presence of high numbers of malignant T cells with CTCL called mycosis fungoides (MF) and Se´zary syndrome (SS) atypical cerebriform nuclei (Se´zary cells) in the peripheral characteristically develop severe immunodeficiency during 6,7 disease progression and consequently patients with advanced blood. As MF and SS will be the main focus of this review, in disease frequently die of infections and not from the tumor the following the term CTCL will exclusively refer to these two burden. For decades, it has been suspected that the malignant clinical variants. T cells actively drive the evolving immunodeficiency to avoid The malignant T cells in both MF and SS typically exhibit the antitumor immunity, yet, the underlying mechanisms remain phenotype of mature CD4 þ memory T cells.2–4 Besides the unclear. The identification of a subset of highly immuno- suppressive regulatory T cells (Tregs) triggered a variety of malignant T cells, the skin lesions also contain a large studies investigating if MF and SS are malignant proliferations proportion of non-malignant inflammatory cells. In early stages of Tregs but seemingly discordant findings have been reported. of MF, the infiltrate primarily consist of non-malignant T helper 1 Here, we review the literature to clarify the role of Tregs in MF (Th1) cells and cytotoxic CD8 þ T cells, which to some degree and SS and discuss the potential mechanisms driving the seem to control the malignant T cells by secreting cytokines as immunodeficiency. interferon (IFN)-a and IFN-g and cytotoxicity directed against Leukemia (2012) 26, 424–432; doi:10.1038/leu.2011.237; 8–12 published online 9 September 2011 malignant T cells expressing tumor-associated antigens. Keywords: cutaneous T-cell lymphoma; Se´zary syndrome; Indeed, it has been shown that high numbers of infiltrating þ immunodeficiency; regulatory T cells; FOXP3; mycosis fungoides CD8 lymphocytes are associated with improved survival.13 As the disease progresses, however, the malignant T cells accumulate concomitant with a decrease in the number of non- 2,13 Introduction malignant immune cells. In particular, there is a stage- dependent decrease in the number and function of activated CD8 þ T cells and natural killer cells resulting in suppression of Cutaneous T-cell lymphoma (CTCL) is the designation for a the hosts’ cellular immunity.2,14–16 Consequently, a hallmark of heterogeneous group of diseases characterized by clonal CTCL patients is that they develop severe immunodeficiency expansion of malignant T cells in the skin. The two predominant during disease progression and in fact patients with advanced clinical forms of CTCL are mycosis fungoides (MF) and Se´zary 1 disease frequently die of infections rather than complications syndrome (SS). MF initially presents as flat erythematous from the tumor burden.17 But, what are the mechanisms patches or plaques covering a limited area of the skin and bear responsible for the evolving immunodeficiency? Are the great resemblance to non-malignant skin disorders like chronic malignant T cells immunosuppressive or is the immuno- eczema, allergic contact dermatitis and large-plaque parapsor- deficiency simply the outcome of a competitive malignant iasis. In these early stages, MF typically exhibits an indolent replacement of benign CD4 þ and CD8 þ T cells? These are clinical behavior and the disease can remain stable for many questions that have attracted much attention in CTCL research years. However, at some point the skin lesions may progress and during the last decades. large intradermal tumors can develop. In advanced disease, the malignant T cells occasionally disseminate to the lymph nodes, peripheral blood and internal organs, which is associated with a 2–4 highly unfavorable prognosis. Sometimes a substantial Early studies on suppressor cells in SS and MF proportion of the malignant T cells become enlargedFa phenomenon referred to as large cell transformation. The In 1976, Broder et al.18 published their seminal paper showing transformation occurs in about 10% of MF patients and is 5 that T cells isolated from the peripheral blood of SS patients associated with a mean survival of only 22 months. The risk of were helper T cells. However, shortly after two studies provided disease progression is significantly higher in more advanced evidence that the malignant T cells from some SS patients had clinical stages demonstrating a change in the nature of the 19,20 19 6 suppressive activity. This finding lead Kansu et al. to disease from indolent to more aggressive. SS is an aggressive propose that SS could develop as an expansion of different T-cell subsets and that malignant T cells from individual patients Correspondence: Dr T Krejsgaard, Department of International Health, therefore could act as helper T cells, suppressor T cells or cells Immunology and Microbiology, University of Copenhagen, Blegdamsvej performing other functions characteristic of T-cell subsets. This 3c, Panum Institute, Building 22.5.38, DK-2200 Copenhagen N, hypothesis was supported by a study published in 1984, which Denmark. þ E-mail: [email protected] showed that CD4 T cells isolated from the peripheral blood of þ Received 6 April 2011; revised 4 July 2011; accepted 13 July 2011; one SS patient were suppressive whereas the CD4 T cells from published online 9 September 2011 two other SS patients possessed neither T helper nor suppressive Tregs in CTCL T Krejsgaard et al 425 activity.21 These early studies essentially highlighted the clear-cut threshold of CD25 expression that accurately separates functional heterogeneity among malignant T-cell populations the two subsets.39 Besides high expression of CD25 and FOXP3, from SS patients and indicated that malignant T cells from some Tregs also typically display surface expression of cytotoxic patients possessed suppressor activity. Yet, the functional T lymphocyte-associated 4 (CTLA-4) and glucocorticoid-induced activity of the lymphocytes was exclusively based on assays tumor necrosis factor receptor-related gene and low expression measuring T-cell-dependent immunoglobulin production by of the interleukin (IL)-7 receptor (CD127) when compared with B cells and the phenotype of the suppressive T cells was poorly conventional T cells.42–46 Current evidence suggest that Tregs characterized. Consequently, these studies did not establish if can be divided into natural Tregs that develop in the thymus and malignant SS cells had the capability to suppress cell-mediated inducible Tregs that develop from naı¨ve CD4 þ CD25À T cells in immunity. Owing to the lack of phenotypic markers and the the periphery on activation in the presence of high levels of difficulties in extracting the malignant T cells from the skin transforming growth factor (TGF)-b and IL-2. Despite their lesions, only a few studies addressed the functional activity of different origin, natural Tregs and inducible Tregs seem to be the malignant T cells in MF at that time. Interestingly, one study functionally and phenotypically similar in many aspects.39,47 reported that tumor-infiltrating lymphocytes (TILs) but not Notably, there exists at least two FOXP3À T-cell subsets with malignant cells isolated from a MF lesion displayed suppressive regulatory activity, namely, T regulatory 1 (Tr1) cells, which properties suggesting that at least a sub-population of TILs may primarily mediate suppression by secreting high levels of IL-10 inhibit antitumor immunity in MF.22 and Th3 cells, which produce large amounts of TGF-b.48 In this review, the term Treg exclusively refers to FOXP3 þ Tregs. Tregs can induce immunosuppression by influencing a variety The discovery of CD4 þ CD25HiFOXP3 þ Tregs of cell types such as CD4 þ and CD8 þ T cells, natural killer cells and antigen-presenting cells. They can exert their The idea of a subset of specialized T cells with immuno- suppressive activity by an arsenal of mechanisms including suppressive activity had been of great scientific interest since the IL-2 deprivation, production of the immunosuppressive cyto- early 1970s but several factors including the failure to identify a kines IL-10 and TGF-b, cytolysis, metabolic disruption and phenotypically distinct subset of suppressive T cells lead to a modulation of the function of antigen-presenting cells.49 It is general decline in the interest from the mid-1980s to the mid- now widely accepted that Tregs are crucial for maintaining 1990s.23 But then, Sakaguchi et al.24 made the landmark peripheral tolerance and preventing inappropriate or excessive discovery that BALB/c athymic nude mice spontaneously immune reactions. However, as a two-edged sword Tregs can developed autoimmune diseases when inoculated with BALB/c also be exploited by tumor cells to suppress antitumor reactions. splenic cell suspensions depleted of CD4 þ CD25 þ T cells. Accordingly, a high proportion of Tregs in the tumor micro- Furthermore, autoimmunity was prevented by reconstitution of environment is associated with poor prognosis in a number of CD4 þ CD25 þ cells within a limited period after transfer of the solid malignancies.50 In T-cell lymphomas, the picture seems CD4 þ CD25À cells indicating that a population of immunosup- more complicated as the tumor cells are of lymphoid origin and, pressive T cells was present in the CD4 þ CD25 þ subset.24 therefore, have the potential to be suppressed by Tregs.
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