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The Journal of Immunology, 2006, 177: 2770-2774.
Copyright © 2006 by The American Association of Immunologists, Inc.

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{dagger}, Kira Dionis*, Liliana Bezrodnik{ddagger}, Alejandro Teper§, Maria Gaillard{ddagger}, Juan Heinrich{ddagger}, Alan M. Krensky*, Ron G. Rosenfeld*,{dagger} and David B. Lewis2,*

* Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305; {dagger} Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon 97239; and {ddagger} Department of Endocrinology and § Department of Pulmonology, Hospital General de Niños Ricardo Gutiérrez, Buenos Aires, Argentina


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
We show that STAT5b is important for the in vivo accumulation of CD4+CD25high T cells with regulatory cell function. A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+CD25high T cells. STAT5bA630P/A630P CD4+CD25high T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+CD25– T cells. Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation. The impact of the STAT5b mutation was selective in that IL-2-mediated up-regulation of the common {gamma}-chain cytokine receptor and perforin, and activation-induced expressions of CD154 and IFN-{gamma} were normal. These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
STAT5a and STAT5b are highly homologous proteins whose role in human immunity remains unclear (1). Murine studies have revealed both overlapping and nonredundant immunological effects in vivo for these proteins (2, 3, 4). Both STAT5a–/– and STAT5b–/– mice have decreased numbers, proliferation of mononuclear leukocytes, and decreased up-regulation of CD25 in response to IL-2. In contrast, only STAT5b–/– mice have a profound defect in NK cell number, cytolytic activity, and IL-2-mediated perforin up-regulation (3, 4). STAT5a–/–STAT5b–/– double-knockout mice have markedly decreased IL-2-dependent T cell proliferation (5) and decreased fetal thymopoiesis (6), as well as an autoimmune diathesis and a reduced number of CD4+CD25high T cells (7, 8). However, the importance of STAT5a vs STAT5b in CD4+CD25high regulatory T cell (Treg)3 immunity in mice or man is unknown.

The roles of IL-2 and IL-2-dependent STAT5 activation in regulating human immune responses in vivo remain poorly understood. The high-affinity IL-2R consists of CD25, which is unique to IL-2R, the IL-2Rbeta1 chain (CD122), and the common {gamma}-chain ({gamma}c), which is also a component of IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R (9). Human CD25 deficiency, which specifically ablates high-affinity signaling by IL-2, results in an abnormal accumulation of lymphocytes in extralymphoid tissues, suggesting perturbed homeostasis, and in increased susceptibility to opportunistic infections (10), which indicates a role for IL-2 in human T cell effector function. This latter role may be species dependent, because blockade of IL-2/IL-2R signaling in mice impairs Treg development and promotes lymphoid hyperplasia and autoimmunity but does not appear to substantially decrease T cell effector function (11, 12, 13).

We examined the immunologic consequence of human STAT5b deficiency focusing on IL-2 and its signal transduction pathway in influencing effector T cell and Treg immunity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Cells

PBMCs were isolated (14) from a 20-year-old STAT5b-deficient (STAT5bA630P/A630P genotype) patient (15), her STAT5bwt/A630P (where wt is wild type) genotype parents, and from age-matched controls who were either healthy or immunosuppressed (control (IS)) similarly as the patient, who was on chronic immunosuppressive glucocorticoid therapy (0.5–1 mg/kg/day prednisone or equivalent for >1 year). Peripheral T cells were either used directly or primed into blasts by incubation with 10 µg/ml PHA (Pharmacia) and 100 U/ml recombinant human IL-2 (Chiron). Complete RPMI 1640 medium (14) was used for in vitro incubation. CD4+CD25high (Treg-enriched) and CD4+CD25– (Treg-depleted) cell populations were isolated from PBMCs using magnetic beads (Miltenyi Biotec) with a final cell purity of 87–95%. T cell blasts were generated as described above from CD4+CD25high or CD4+CD25– T cells.

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 Laboratories) 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 µg/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-{gamma} and CD69 expression

PBMCs were stimulated with 10 µg/ml Staphylococcus aureus enterotoxin B (SEB) (Toxin Technologies) or CD3/CD28 mAb microbeads (Miltenyi Biotec) for 16 h, with 10 µg/ml brefeldin A (Sigma-Aldrich) added for the last 5 h. Cells were analyzed as described (14) after staining with PE-Cy5-CD4, allophycocyanin (AC)-CD8, PE-CD69, and FITC-IFN-{gamma} mAb.

CD154 expression

PBMCs (1 x 106) were treated with CD3/CD28 mAb microbeads for 6 h and stained with CD154 mAb (clone 5C8) or an isotype control and PE-conjugated goat-anti-mouse IgG (Caltag Laboratories).

CD25 and {gamma}c staining

PBMCs (5 x 105/well) were incubated in 96-well round-bottom microtiter plates coated with 3.5 µg/ml purified CD3 mAb 64.1 (Bristol-Myers Squibb) 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 PE-{gamma}c mAbs.

Perforin expression by CD8+ T cells

PBMCs incubated with or without IL-2 (1.0 x 103 U/ml) for 3 days were permeabilized/fixed (BD Biosciences) and stained with FITC-perforin and PE-CD8 mAbs.

Annexin-V staining and propidium iodide staining

T cell blasts were incubated with annexin V-FITC and propidium iodide (Oncogene Sciences) and AC-CD4 mAb.

Intracellular staining for Foxp3

Purified CD4+CD25high or CD4+CD25– T cells or their blasts were fixed/permeabilized, blocked with 2% normal rat serum, and stained with FITC-Foxp3 mAb (eBioscience) or isotype control mAb for 30 min.

Treg-mediated suppression of CD4 T cell proliferation

CD4+CD25high T cells (3.75 x 103/well) were incubated in 96-well round-bottom plates with either a 1:1 or 1:4 ratio of autologous or allogeneic CD4+CD25– T cells, 3.75 x 104 allogeneic irradiated (4000 rad) APCs (PBMCs depleted of CD3+ T cells using magnetic beads from StemCell Technologies), and 5.0 µg/ml purified HIT3a CD3 mAb (BD Biosciences). Control conditions lacked either CD4+CD25high or CD4+CD25– T cells. [3H]Thymidine (1.0 µCi/well) was added during the last 16 h of a 7-day culture, and cellular incorporation was determined by liquid scintillation counting.

Treg cytotoxicity assay

Autologous CD4+CD25– T cells were activated with 2 µg/ml PHA for 3 days, labeled with 51Cr, and added at 1 x 103/well to 96-well round-bottom plates. CD4+CD25high T cells or their blasts were added as effector cells, plates were incubated at 37°C for 4 h, and 100 µl of supernatant was counted for gamma irradiation.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
We investigated the immunological phenotype of a 20-year-old woman with severe growth hormone insensitivity due to a homozygous missense STAT5b mutation (A630P) (15). STAT5bA630P/A630P T cells (Fig. 1A) had undetectable levels of STAT5b protein and normal levels of STAT5a, similar to those of STAT5bA630P/A630P fibroblasts or EBV-transformed B cell lines (15, 16). Immunological evaluation between 3 and 19 years of age (Fig. 1B) revealed modest but consistently reduced circulating numbers of CD4 and CD8 T cells, low to normal levels of NK cells, and normal to elevated levels of B cells. In contrast, serum IgG and IgA concentrations were persistently elevated (Fig. 1B), suggesting immune dysregulation. T cell proliferation to mitogens, specific Ags, and CD3 mAb was normal at 10 and 16 years of age despite the T cell lymphopenia, and specific Ab titers to several protein Ags were detectable, indicating that T cell proliferation and T cell-dependent Ab formation were intact (data not shown). At 7 years of age she developed lymphocytic interstitial pneumonia, which is associated with autoimmunity, but only had two major infectious complications — severe varicella-zoster virus infection and Pneumocystis jiroveci pneumonia — that occurred after receiving potent immunosuppressive therapy for the lymphoid pneumonitis.


Figure 1
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  		FIGURE 1. Decreased STAT5b and CD25 expression by STAT5bA630P/A630P T cell blasts is associated with chronic lymphopenia and hypergammaglobulinemia. A. Western blot showing STAT5a and STAT5b expression in T cell blasts. B. The numbers of CD4 and CD8 T cells, NK cells (CD56+ lymphocytes), and B cells (CD19+) were determined by flow cytometry and complete blood counts with differentials. Total serum IgG and IgA levels that were determined in parallel by nephelometry are shown. Normal values (mean ± 1 SD) 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 STAT5bA630P/A630P, STAT5bwt/A630P, and control (IS) subjects were 231, 721, and 1115, respectively. D, Annexin-V-FITC vs propidium iodide staining of control (IS) and STAT5bA630P/A630P CD4 T cell blasts.

 
Because STAT5 proteins have a well-defined role in enhancing CD25 gene transcription in response to IL-2 (17), we compared CD25 expression by STAT5b-deficient or control PHA- and IL-2-stimulated CD4 T cell blasts. STAT5bA630P/A630P CD4 T cell blasts expressed ~20% of the amount of surface CD25 compared with control cells, based on the mean fluorescence intensity measurements (Fig. 1C), a phenotype that would be expected to reduce IL-2-mediated signaling. Interestingly, STAT5bwt/A630P T cell blasts also had a modest but consistently lower CD25 expression than did control cells (Fig. 1C). A substantially greater percentage of the STAT5bA630P/A630P T cell blasts was apoptotic as compared with control cells (Fig. 1D), and this likely accounted for the poor IL-2-mediated expansion of STAT5bA630P/A630P T cells from PBMCs compared with T cells from the STAT5bA630P/wt parents or from control (IS) donors (A. C. Cohen and D. B. Lewis, unpublished observations).

We next evaluated freshly isolated STAT5bA630P/A630P T cells for activation- and IL-2-dependent protein expression and effector function. CD154 (Fig. 2A), CD69, and IFN-{gamma} expression in response to SEB (Fig. 2B) or CD3/CD28 mAb stimulation (data not shown) and perforin up-regulation in response to IL-2 (Fig. 2C) by STAT5bA630P/A630P T cells were similar to those of T cells from healthy controls or control (IS) donors. As with T cell blasts, CD25 up-regulation by STAT5bA630P/A630P CD4 T cells in response to IL-2 was decreased compared with control T cells, whereas the up-regulation by IL-2 of {gamma}c was normal (Fig. 2D). These results indicated that STAT5b deficiency selectively impaired the up-regulation of CD25 by IL-2 in freshly isolated T cells but spared other IL-2- and activation-dependent functions.


Figure 2
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  		FIGURE 2. Impairment of CD25 expression but not effector function by freshly isolated T cells in STAT5b deficiency. A, CD154 surface expression (dark gray trace) or control isotype staining (light gray trace) by lymphocytes; the upper right-hand corner indicates the percentage of positive cells. B, IFN-{gamma} and CD69 expression by CD4 and CD8 T cells after incubation with or without SEB. C, IL-2 mediated perforin expression by CD8 T cells. Shown is the percentage of cells expressing perforin. D, CD25 and {gamma}c surface expression by CD4 T cells after stimulation with CD3 mAb alone or in combination with IL-2.

 
We next determined whether STAT5b deficiency had an impact on the coexpression by CD4 T cells of CD25 and the transcription factor forkhead box P3 (FoxP3), which identifies cells highly enriched in Treg function (11, 18). STAT5bA630P/A630P CD4+CD25high T cells did not express detectable Foxp3 protein, and this level of expression was also very low for freshly isolated STAT5bwt/A630P CD4+CD25high T cells as compared with that for controls (Fig. 3). The percentage of STAT5bA630P/A630P CD4+ T cells that were CD25high was also only ~10% and ~25% of that of control (IS) and STAT5bwt/A630P donors, respectively. Foxp3 expression by T cell blasts generated in vitro from STAT5bA630P/A630P CD4+CD25high T cells remained undetectable, and CD25 expression was also lower relative to the basal level, whereas control (IS) CD4+CD25high T cell blasts retained high levels of both proteins. As expected, CD4+CD25– T cells or blasts from all subjects lacked detectable Foxp3 (data not shown), consistent with the CD4+ Tregs being contained mainly in the CD25high subset. Interestingly, STAT5bwt/A630P CD4+CD25high T cell blasts acquired Foxp3 levels similar to those of control (IS) blasts, indicating that STAT5b haplo insufficiency did not impair responsiveness to activation- and IL-2-mediated signals for increased Foxp3 (19). Therefore, complete STAT5b deficiency impaired the peripheral accumulation of CD4+CD25high Tregs and their generation in vitro (18, 20). Whether this decreased accumulation in vivo is the result of decreased intrathymic and/or peripheral Treg generation or, once generated, by impaired Treg survival or homeostatic proliferation, remains to be determined.


Figure 3
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  		FIGURE 3. Decreased Foxp3 expression by CD4+CD25high T cells in STAT5b deficiency. CD25 and Foxp3 expression (open histograms) was analyzed by flow cytometry for CD4+CD25high T cells directly ex vivo and after their propagation in vitro as T cell blasts. Filled histograms indicate isotype control mAb staining.

 
The capacity of STAT5b-deficient vs control CD4+CD25high T cells to suppress autologous or allogeneic CD4+CD25– T cells was examined using a standard assay (21). CD4+CD25– T cells proliferated in response to allogeneic stimulation in the absence of CD4+CD25high T cells as expected (21). Both control (IS) and STAT5bwt/A630P Treg-enriched cells suppressed proliferation of autologous and allogeneic CD4+CD25– T cells in a dose-dependent fashion, although the suppressive ability of the STAT5bwt/A630P CD4+CD25high T cells was consistently lower than that of control (IS) cells (Fig. 4, A and B). In contrast, STAT5bA630P/A630P CD4+CD25high T cells proliferated after allogeneic stimulation. This proliferation after allogeneic stimulation is consistent with Foxp3 acting directly to inhibit T cell effector function, e.g., by inhibiting cytokine gene transcription (22). Importantly, STAT5bA630P/A630P CD4+CD25high T cells did not suppress the proliferation of autologous or allogeneic CD4+CD25– T cells. Moreover, STAT5bA630P/A630P CD4+CD25high T cells propagated as blasts failed to acquire Treg activity in this assay, whereas blasts from STAT5bwt/A630P CD4+CD25high T cells increased their Treg activity (Fig. 4A). Proliferation of STAT5bA630P/A630P CD4+CD25– T cells was suppressible by control CD4+CD25high T cells (Fig. 4B). Thus, the loss of STAT5b signaling affected Foxp3 expression by CD4 T cells and resulted in impaired Treg suppressive function. The low to undetectable levels of Foxp3 expression by STAT5b-deficient CD4+CD25high T cells might directly impair their Treg function or merely serve as a marker for impaired Foxp3-independent pathways of Treg activity.


Figure 4
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  		FIGURE 4. Decreased Treg activity by CD4+CD25high (CD4+CD25hi) T cells in STAT5b deficiency. A, [3H]Thymidine incorporation by autologous CD4+CD25– (CD4+CD25neg) T cells or their T cell blasts alone (filled bars), CD4+CD25high T cells or their T cell blasts alone (light gray bars), and mixtures of CD4+CD25– and CD4+CD25high T cells or their T cell blasts at ratios of 1:1 (dark gray bars) and 4:1 (open bars), respectively. B, [3H]Thymidine incorporation by CD4+CD25– T cells incubated with allogeneic CD4+CD25high T cells from a control or from the STAT5bA630P/A630P patient, as indicated. For each condition, the mean ± SEM for eight replicates is shown. C, Percentage of cell lysis of 51Cr-labeled CD4+CD25– T cells after incubation with the indicated ratio of autologous CD4+CD25high and CD4+CD25– subsets or T cell blasts derived from these cell populations. Mean ± SEM for three replicates are shown.

 
Finally, we determined whether STAT5b deficiency also compromised Treg cell-mediated cytotoxicity of non-Treg targets (23). As expected, little or no killing of activated autologous CD4+ T cells occurred when control (IS), STAT5bA630P/A630P, or STAT5bwt/A630P CD4+CD25– T cells or their T cell blasts were used as effectors. Both control (IS) and STAT5bwt/A630P CD4+CD25high T cells killed autologous CD4+CD25– T cell targets in a dose-dependent manner. In contrast, freshly isolated STAT5bA630P/A630P CD4+CD25high T cells failed to kill either when used directly or as T cell blasts (Fig. 4C). Cytotoxicity by STAT5bwt/A630P CD4+CD25high T cells and their blasts was also consistently lower than that by control (IS) effector cells.

Our findings indicate an important and unexpected role in humans for STAT5b signaling in CD4+CD25high Treg immunity and, in contrast, only a modest impact on the size of the peripheral T cell compartment and its effector function. This Treg deficiency was associated with a role for STAT5b that was not redundant with that of STAT5a in the up-regulation of CD25 gene expression by IL-2. The major immunological phenotype of STAT5b haplo insufficiency was also on the up-regulation of CD25 by IL-2 and on Treg immunity. In contrast to mice (12), the phenotype of human CD25 deficiency (10) and ability of CD25 mAb to block allograft rejection suggest that IL-2R signaling in humans may also be important for T cell effector function in vivo. Our results suggest that optimal human Treg immunity, but not most T cell effector functions, requires either higher levels of IL-2 signaling and/or a unique transcriptional effect of STAT5b. If high levels of IL-2 signaling are required for human Treg immunity, it is plausible that the STAT5b-dependent up-regulation of CD25 by IL-2 may play an important role in achieving such signaling.


   Acknowledgments
 
We are grateful to Dr. Jennifer Frankovich for help in obtaining blood samples from patients and their family members and to Dr. David Randolph for critiquing the manuscript.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
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. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grant K08 AI057961-01 (to A.C.C), an American Society of Hematology Fellow Basic Science Award (to A.C.C), the Jeffrey Modell Center for Primary Immunodeficiency (to D.B.L), and a Berry Fellowship in Children’s Health (to K.C.N.). Back

2 Address correspondence and reprint requests to Dr. David B. Lewis, Division of Immunology and Transplantation Biology, Center for Clinical Sciences Research Building, Room 2115b, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305-5164. E-mail address: dblewis{at}stanford.edu Back

3 Abbreviations used in this paper: Treg, CD4+CD25high regulatory T cell; AC, allophycocyanin; Foxp3, forkhead box P3; {gamma}c, common {gamma} chain; control (IS), control treated with immunosuppressive glucocorticoid therapy; SEB, Staphylococcus aureus enterotoxin B; wt, wild type. Back

Received for publication March 7, 2006. Accepted for publication June 29, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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Expression of ICOS on Human Melanoma-Infiltrating CD4+CD25highFoxp3+ T Regulatory Cells: Implications and Impact on Tumor-Mediated Immune Suppression
J. Immunol., March 1, 2008; 180(5): 2967 - 2980.
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V. Sanchez-Guajardo, C. Tanchot, J. T. O'Malley, M. H. Kaplan, S. Garcia, and A. A. Freitas
Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6
J. Immunol., June 15, 2007; 178(12): 7550 - 7556.
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 Int ImmunolHome page
J. Yates, F. Rovis, P. Mitchell, B. Afzali, J.-S Tsang, M. Garin, R. Lechler, G. Lombardi, and O. Garden
The maintenance of human CD4+CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro
Int. Immunol., June 1, 2007; 19(6): 785 - 799.
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