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Cells in Human Stat5b Deficiency T High Cutting Edge: Decreased Accumulation and Regulatory Function of CD4 +CD25high T Cells in Human STAT5b Deficiency This information is current as Aileen C. Cohen, Kari C. Nadeau, Wenwei Tu, Vivian Hwa, of September 26, 2021. Kira Dionis, Liliana Bezrodnik, Alejandro Teper, Maria Gaillard, Juan Heinrich, Alan M. Krensky, Ron G. Rosenfeld and David B. Lewis J Immunol 2006; 177:2770-2774; ; doi: 10.4049/jimmunol.177.5.2770 Downloaded from http://www.jimmunol.org/content/177/5/2770 References This article cites 22 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/177/5/2770.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY CUTTING EDGE Cutting Edge: Decreased Accumulation and Regulatory Function of CD4؉CD25high T Cells in Human STAT5b Deficiency1 Aileen C. Cohen,* Kari C. Nadeau,* Wenwei Tu,* Vivian Hwa,† Kira Dionis,* Liliana Bezrodnik,‡ Alejandro Teper,§ Maria Gaillard,‡ Juan Heinrich,‡ Alan M. Krensky,* Ron G. Rosenfeld,*† and David B. Lewis2* ϩ We show that STAT5b is important for the in vivo accu- CD4 CD25high regulatory T cell (Treg)3 immunity in mice or ؉ mulation of CD4 CD25high T cells with regulatory cell man is unknown. function. A patient homozygous for a missense A630P The roles of IL-2 and IL-2-dependent STAT5 activation in Downloaded from STAT5b mutation displayed immune dysregulation and regulating human immune responses in vivo remain poorly un- ؉ decreased numbers of CD4 CD25high T cells. derstood. The high-affinity IL-2R consists of CD25, which is -A630P/A630P ؉ high unique to IL-2R, the IL-2R␤1 chain (CD122), and the com STAT5b CD4 CD25 T cells had low ex- ␥ ␥ pression of forkhead box P3 and an impaired ability to mon -chain ( c), which is also a component of IL-4R, IL-7R, ؉ ؊ suppress the proliferation of or to kill CD4 CD25 T IL-9R, IL-15R, and IL-21R (9). Human CD25 deficiency, which specifically ablates high-affinity signaling by IL-2, results http://www.jimmunol.org/ cells. Expression of CD25, a component of the high-affin- in an abnormal accumulation of lymphocytes in extralymphoid ity IL-2R, was also reduced in response to IL-2 or after in tissues, suggesting perturbed homeostasis, and in increased sus- vitro propagation. The impact of the STAT5b mutation ceptibility to opportunistic infections (10), which indicates a was selective in that IL-2-mediated up-regulation of the ␥ role for IL-2 in human T cell effector function. This latter role common -chain cytokine receptor and perforin, and ac- may be species dependent, because blockade of IL-2/IL-2R sig- ␥ tivation-induced expressions of CD154 and IFN- were naling in mice impairs Treg development and promotes lym- normal. These results indicate that STAT5b propagates phoid hyperplasia and autoimmunity but does not appear to an important IL-2-mediated signal for the in vivo accu- substantially decrease T cell effector function (11–13). by guest on September 26, 2021 mulation of functional regulatory T cells. The Journal of We examined the immunologic consequence of human Immunology, 2006, 177: 2770–2774. STAT5b deficiency focusing on IL-2 and its signal transduction pathway in influencing effector T cell and Treg immunity. TAT5a and STAT5b are highly homologous proteins whose role in human immunity remains unclear (1). Murine studies have revealed both overlapping and Materials and Methods S Cells nonredundant immunological effects in vivo for these proteins Ϫ Ϫ Ϫ Ϫ (2–4). Both STAT5a / and STAT5b / mice have decreased PBMCs were isolated (14) from a 20-year-old STAT5b-deficient (STAT5bA630P/A630P genotype) patient (15), her STAT5bwt/A630P (where wt is numbers, proliferation of mononuclear leukocytes, and de- wild type) genotype parents, and from age-matched controls who were either creased up-regulation of CD25 in response to IL-2. In contrast, healthy or immunosuppressed (control (IS)) similarly as the patient, who was Ϫ Ϫ only STAT5b / mice have a profound defect in NK cell num- on chronic immunosuppressive glucocorticoid therapy (0.5–1 mg/kg/day pred- nisone or equivalent for Ͼ1 year). Peripheral T cells were either used directly or ber, cytolytic activity, and IL-2-mediated perforin up-regula- ␮ Ϫ/Ϫ Ϫ/Ϫ primed into blasts by incubation with 10 g/ml PHA (Pharmacia) and 100 tion (3, 4). STAT5a STAT5b double-knockout mice U/ml recombinant human IL-2 (Chiron). Complete RPMI 1640 medium (14) was used for in vitro incubation. CD4ϩCD25high (Treg-enriched) and have markedly decreased IL-2-dependent T cell proliferation ϩ Ϫ (5) and decreased fetal thymopoiesis (6), as well as an autoim- CD4 CD25 (Treg-depleted) cell populations were isolated from PBMCs us- ϩ high ing magnetic beads (Miltenyi Biotec) with a final cell purity of 87–95%. T cell mune diathesis and a reduced number of CD4 CD25 T blasts were generated as described above from CD4ϩCD25high or cells (7, 8). However, the importance of STAT5a vs STAT5b in CD4ϩCD25Ϫ T cells. *Department of Pediatrics, Stanford University School of Medicine, Stanford, California Jeffrey Modell Center for Primary Immunodeficiency (to D.B.L), and a Berry Fellowship 94305; †Department of Pediatrics, Oregon Health and Sciences University, Portland, Or- in Children’s Health (to K.C.N.). egon 97239; and ‡Department of Endocrinology and §Department of Pulmonology, Hos- 2 Address correspondence and reprint requests to Dr. David B. Lewis, Division of Immu- pital General de Nin˜os Ricardo Gutie´rrez, Buenos Aires, Argentina nology and Transplantation Biology, Center for Clinical Sciences Research Building, Received for publication March 7, 2006. Accepted for publication June 29, 2006. Room 2115b, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305-5164. E-mail address: [email protected] The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. 3 Abbreviations used in this paper: Treg, CD4ϩCD25high regulatory T cell; AC, allophy- Section 1734 solely to indicate this fact. cocyanin; Foxp3, forkhead box P3; ␥c, common ␥ chain; control (IS), control treated with immunosuppressive glucocorticoid therapy; SEB, Staphylococcus aureus enterotoxin B; wt, 1 This work was supported by National Institutes of Health Grant K08 AI057961-01 (to wild type. A.C.C), an American Society of Hematology Fellow Basic Science Award (to A.C.C), the Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 2771 Ab staining and flow cytometric analysis Staining with mAbs (purchased from Caltag Laboratories or BD Biosciences, unless indicated otherwise) or appropriate mouse isotype controls (Caltag Lab- oratories) was performed (14) and analyzed using a FACScan flow cytometer and CellQuest software (BD Biosciences). Paraformaldehyde-fixed cells were used, except for annexin-V and propidium iodide staining. Western blotting Protein (15 ␮g/lane) from T cell blasts was electrophoresed, blotted, and probed with STAT5a (L20; rabbit polyclonal IgG) or STAT5b (G-2; mouse mAb IgG1) Abs (Santa Cruz Biotechnology) as described (15). IFN-␥ and CD69 expression PBMCs were stimulated with 10 ␮g/ml Staphylococcus aureus enterotoxin B (SEB) (Toxin Technologies) or CD3/CD28 mAb microbeads (Miltenyi Bio- tec) for 16 h, with 10 ␮g/ml brefeldin A (Sigma-Aldrich) added for the last 5 h. Cells were analyzed as described (14) after staining with PE-Cy5-CD4, allo- phycocyanin (AC)-CD8, PE-CD69, and FITC-IFN-␥ mAb. CD154 expression PBMCs (1 ϫ 106) were treated with CD3/CD28 mAb microbeads for6hand Downloaded from stained with CD154 mAb (clone 5C8) or an isotype control and PE-conjugated goat-anti-mouse IgG (Caltag Laboratories). CD25 and ␥c staining PBMCs (5 ϫ 105/well) were incubated in 96-well round-bottom microtiter ␮ plates coated with 3.5 g/ml purified CD3 mAb 64.1 (Bristol-Myers Squibb) A630P/A630P FIGURE 1. Decreased STAT5b and CD25 expression by STAT5b http://www.jimmunol.org/ with or without 10 U/ml recombinant human IL-2 for 24 h. T cell blasts or CD3 mAb-activated PBMCs were stained with PE-Cy5-CD4, AC-CD25, and T cell blasts is associated with chronic lymphopenia and hypergammaglobu- PE-␥c mAbs. linemia. A. Western blot showing STAT5a and STAT5b expression in T cell blasts. B. The numbers of CD4 and CD8 T cells, NK cells (CD56ϩ lympho- ϩ Perforin expression by CD8 T cells cytes), and B cells (CD19ϩ) were determined by flow cytometry and complete ϫ 3 blood counts with differentials. Total serum IgG and IgA levels that were de- PBMCs incubated with or without IL-2 (1.0 10 U/ml) for 3 days were Ϯ permeabilized/fixed (BD Biosciences) and stained with FITC-perforin and PE- termined in parallel by nephelometry are shown. Normal values (mean 1 SD) CD8 mAbs. for age are indicated. C, CD25 expression by CD4 T cell blasts. The CD25 mean fluorescence intensity values of CD4 T cell blasts of the Annexin-V staining and propidium iodide staining STAT5bA630P/A630P, STAT5bwt/A630P, and control (IS) subjects were 231, 721, and 1115, respectively.
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