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Cells Intestinal Lamina Propria As Regulatory T Cells in Human Bright CD25 +CD4

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Cells Intestinal Lamina Propria As Regulatory T Cells in Human Bright CD25 +CD4 The Journal of Immunology CD4؉CD25bright T Cells in Human Intestinal Lamina Propria as Regulatory Cells1 Shin Makita,* Takanori Kanai,2* Shigeru Oshima,* Koji Uraushihara,* Teruji Totsuka,* Taisuke Sawada,* Tetsuya Nakamura,* Kazutaka Koganei,† Tsuneo Fukushima,† and Mamoru Watanabe* It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of inflammatory bowel disease. In this study, we demonstrate that the CD4؉CD25bright T cells reside in the human intestinal lamina propria (LP) and functionally retain regulatory activities. All human LP CD4؉ T cells regardless of CD25 expression constitutively expressed CTLA-4, glucocorticoid-induced TNFR family-related protein, and Foxp3 and proliferate poorly. Although LP CD4؉CD25؊ T cells showed an activated and anergic/memory phenotype, they did not retain regulatory activity. In LP CD4؉CD25؉ T cells, however, cells expressing CD25 at high levels (CD4؉CD25bright) suppressed the proliferation and various cytokine productions of CD4؉CD25؊ T cells. LP CD4؉CD25bright T cells by themselves produced fewer amounts of IL-2, IFN-␥, and IL-10. Interestingly, LP CD4؉CD25bright T cells with regulatory T activity were significantly increased in patients with active inflammatory bowel disease. These results suggest that CD4؉CD25bright T cells found in the normal and inflamed intestinal mucosa selectively inhibit the host immune response and therefore may contribute to the intestinal immune homeostasis. The Journal of Immunology, 2004, 173: 3119–3130. he gastrointestinal tract is home to the largest number of of an intact immune system for the intestinal homeostasis is re- leukocytes in the body as well as being the site where vealed by the fact that a number of immune manipulations, includ- these cells encounter abundant exogenous stimuli. De- ing deletion of cytokine genes and alterations in T subsets, lead T R spite this potential immune stimulus, it is well known that immune to the development of an animal model of inflammatory bowel responses in the intestine remain in a state of controlled inflam- disease (IBD) (10–12). Evidence emerging from these studies sug- mation (1). Regulation of the immune response here is a balance gests that pathogenic responses in the intestine are derived by res- between the need to mount protective immunity toward pathogens ident bacteria and are controlled by a functionally specialized pop- while not activating damaging inflammatory responses to the ulation of T cells in the GALT (13). by guest on October 1, 2021. Copyright 2004 Pageant Media Ltd. R plethora of harmless Ags present, including those derived from A variety of TR cells that display regulatory function in vitro or resident bacteria (2–4). To maintain the intestinal homeostasis, in vivo have been described. These can be subdivided into different including immunological tolerance, functionally distinct subsets subsets based on the expression of cell surface markers, production have been clearly defined in T cells (5, 6). Among these subsets, of cytokines, and mechanisms of action. Recent studies focused on the regulatory T (T )3 cell subset down-regulates immune re- ϩ R CD25 as the best marker for CD4 TR cells in mice and humans sponses for both foreign and self-Ags and effectively participates (14–16). CD4ϩCD25ϩ T cells, which constitute ϳ10% of periph- in the suppression of autoimmune disorders (7–9). The importance eral murine and human CD4ϩ T cells, express CTLA-4 (17–20), glucocorticoid-induced TNFR family-related protein (GITR) (21, http://classic.jimmunol.org 22), and the forkhead/winged helix transcription factor Foxp3 (23– *Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and †Department of Surgery, Yokohama City 25). Although autoimmune diseases, including IBD, can be in- Hospital, Yokohama, Japan duced by reconstituting immunodeficient mice with peripheral ϩ ϩ ϩ Received for publication December 10, 2003. Accepted for publication June 23, 2004. CD4 T cells, which have been depleted of CD4 CD25 (26) or ϩ ϩ The costs of publication of this article were defrayed in part by the payment of page CD4 GITR T cells (27), not only the existence of human intes- charges. This article must therefore be hereby marked advertisement in accordance tinal CD4ϩCD25ϩ T cells in normal or diseased condition but with 18 U.S.C. Section 1734 solely to indicate this fact. R Downloaded from also their role in the pathogenesis of IBD are largely unknown. 1 This study was supported in part by Grants-in-Aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research and Creative Scientific Research Conversely, several findings, for example. the evidence of the ac- ϩ ϩ ϩ from the Japanese Ministry of Education, Culture, Sports, Science and Technology; cumulated CD25 , CD69 , and CD71 (transferrin receptor) the Japanese Ministry of Health, Labor and Welfare; the Japan Medical Association; cells, indicate an increased state of activation of the T cell system Foundation for Advancement of International Science; Terumo Life Science Foun- dation; Ohyama Health Foundation; Yakult Bio-Science Foundation; and Research in IBD (28). Although intestinal lamina propria (LP) T cells are Fund of Mitsukoshi Health and Welfare Foundation. already preactivated, the activation is further increased in both the 2 Address correspondence and reprint requests to Dr. Takanori Kanai, Department of circulation and mucosa from IBD patients as determined by sev- Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail ad- eral activation markers as compared with those from normal indi- dress: [email protected] viduals (29). Furthermore, this activated phenotype is increased in 3 Abbreviations used in this paper: TR, regulatory T; IBD, inflammatory bowel dis- involved compared with uninvolved areas or control tissue (29), ease; GITR, glucocorticoid-induced TNFR family-related protein; LP, lamina propria; being so far believed that these activated CD4ϩCD25ϩ cells LPMC, lamina propria mononuclear cell; MMC, mitomycin C; CD, Crohn’s disease; UC, ulcerative colitis; rh, recombinant human; CT, critical threshold; PB, peripheral should be pathogenic for the development of IBD. These conflict- blood; MFI, mean fluorescence intensity. ing findings prompted us to determine whether or not the LP Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 ϩ bright 3120 LP CD4 CD25 TR CELLS CD4ϩCD25ϩ T cells in IBD patients were pathogenic (effector) or BNI3, PE-conjugated anti-CTLA-4; MQ1-17, PE-conjugated protective (TR) in this study. anti-IL-2; JES3-19F1, PE-conjugated anti-IL-10; 4S.B3, PE- and Furthermore, there is much other evidence showing that 1) the FITC-conjugated anti-IFN-␥ (BD Pharmingen, San Diego, CA); peripheral CD4ϩCD25Ϫ T cell population also possesses some 110416, PE-conjugated anti-human GITR (R&D Systems, regulatory activity (26, 30–34), 2) anergic/memory T cells have Minneapolis, MN). regulatory properties (35–38), and 3) LP CD4ϩ T lymphocytes, Purified recombinant human IL-2 (rhIL-2; kindly provided by regardless of CD25 expression, are generally memory T cells, and Shionogi Pharmaceutical, Osaka, Japan), purified anti-human CD3 hyporesponsive to TCR-mediated proliferative signals (39, 40), mAb (HIT3a; BD Pharmingen), Con A (Sigma-Aldrich), PHA indicating these cells could be highly differentiated effector or ef- (Sigma-Aldrich), and mitomycin C (MMC, Sigma-Aldrich) were fector memory T cells (41, 42) with a raised threshold of activation used for in vitro coculture assay. that prevents immune responses to harmless intraluminal Ags. In the present study, we investigate the existence and the role of Isolation of LP mononuclear cells (LPMCs) from intestinal the human LP CD4ϩCD25bright as well as CD4ϩCD25ϩ and mucosa CD4ϩCD25Ϫ T cells. We demonstrate here that human LP CD4ϩ LPMCs were isolated from surgically resected intestinal speci- T cells from the normal intestine, regardless of CD25 expression, mens using enzymatic techniques as previously described (43). express other regulatory markers, CTLA-4, GITR, and Foxp3, and Briefly, the dissected mucosa was incubated in calcium and mag- show anergic and memory features, but only CD4ϩCD25bright LP nesium-free HBSS containing 2.5% FBS and 1 mM DTT (Sigma- T cells retain TR function, which can mediate potent suppression Aldrich) to remove mucus. The mucosa was then incubated in of autologous T cell proliferation and various cytokine produc- medium containing 0.75 mM EDTA (Sigma-Aldrich) for 60 min at tions, such as IFN-␥ and IL-2. Furthermore, we show here that 37°C. During this treatment, intraepithelial lymphocytes and epi- these TR cells are significantly increased in patients with thelial cells were released from the tissue and tissues containing active IBD. LPMCs were collected and incubated in medium containing 0.02% collagenase (Worthington Biochemical, Freehold, NJ). The frac- Materials and Methods tion was pelleted twice through a 40% isotonic percoll solution and Patients and samples the cells were then centrifuged over a Ficoll-Hypaque density gra- dient (40% and 60%). The purity of resulting LPMCs was ana- Normal mucosal samples were obtained from macroscopically
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