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The Journal of Immunology, 2006, 177: 6598-6602.
Copyright © 2006 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: The Phosphoinositide 3-Kinase p110{delta} Is Critical for the Function of CD4+CD25+Foxp3+ Regulatory T Cells1

Daniel T. Patton2,*, Oliver A. Garden2,3,{dagger},{ddagger}, Wayne P. Pearce§, Louise E. Clough, Clare R. Monk{dagger}, Eva Leung{dagger}, Wendy C. Rowan||, Sara Sancho#, Lucy S. K. Walker, Bart Vanhaesebroeck§,** and Klaus Okkenhaug3,*

* Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom; {dagger} Regulatory T Cell Laboratory, Department of Immunology, Imperial College London, London, United Kingdom; {ddagger} Department of Veterinary Clinical Sciences, The Royal Veterinary College, Hatfield, United Kingdom; § Cell Signalling Laboratory, Ludwig Institute for Cancer Research, London, United Kingdom; Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom; || GlaxoSmithKline, Stevenage, United Kingdom; # Department of Medicine, University of Fribourg, Fribourg, Switzerland; and ** Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
CD4+CD25+Foxp3+ regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance by inhibiting the expansion and function of conventional T cells. Treg development and homeostasis are regulated by the Ag receptor, costimulatory receptors such as CD28 and CTLA-4, and cytokines such as IL-2, IL-10, and TGF-beta. Here we show that the proportions of Tregs in the spleen and lymph nodes of mice with inactive p110{delta} PI3K (p110{delta}D910A/D910A) are reduced despite enhanced Treg selection in the thymus. p110{delta}D910A/D910A CD4+CD25+Foxp3+ Tregs showed attenuated suppressor function in vitro and failed to secrete IL-10. In adoptive transfer experiments, p110{delta}D910A/D910A T cells failed to protect against experimental colitis. The identification of p110{delta} as an intracellular signaling protein that regulates the activity of CD4+CD25+Foxp3+ Tregs may facilitate the further elucidation of the molecular mechanisms responsible for Treg-mediated suppression.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
The contribution of CD4+CD25+Foxp3+ regulatory T cells (Tregs)4 to the maintenance of peripheral tolerance is now well established. In particular, Tregs are essential for the maintenance of peripheral tolerance to both self-Ags and the intestinal flora and contribute to the homeostatic control of T cell numbers, allograft tolerance, and the modulation of immune responses against pathogens and neoplasms (1, 2). Although the expression of CD25 by CD4+ T cells was originally used to identify the Treg population (3), a more definitive marker for this population is the transcription factor Foxp3, the expression of which is both necessary and sufficient to confer a Treg phenotype (4, 5, 6, 7, 8). In the thymus, conventional T cells are selected on the basis of low avidity for self-Ags, whereas thymocytes with high avidity for self-Ags are eliminated. In a revised model of T cell development, T cells with intermediate avidity for self-Ags survive and develop into Tregs (9, 10). Once the cells move to the periphery, Treg homeostasis is achieved by interactions with self-Ag and B7 on APCs as well as by IL-2 secreted by Th cells (11, 12, 13, 14, 15).

The class IA PI3Ks are heterodimeric inositide lipid kinases that control various aspects of immune cell function (16). The p110{delta} isoform of PI3K is highly enriched in leukocytes and is an important signaling protein in lymphocytes (16). In T cells, PI3K can be activated by the TCR, CD28, IL-2R, and chemokine receptors (16, 17). We have previously shown that p110{delta} is the main PI3K isoform activated by the TCR (18). T cells expressing a kinase-inactive knock-in form of p110{delta} (p110{delta}D910A/D910A) show impaired proliferation and reduced production of IL-2, IL-4, and IFN-{gamma} in response to stimulation with Ag (18, 19). In addition, p110{delta}D910A/D910A mice develop spontaneous colitis (18). Similar pathological lesions have been described for mouse models of colitis caused by impaired Treg function (2). We therefore considered that Treg development and/or function might be impaired in p110{delta}-deficient mice.

In this study we show that in p110{delta}D910A/D910A mice an increased proportion of thymocytes develop into Tregs. By contrast, the lymph nodes and spleen contained reduced proportions of Foxp3+ T cells. These p110{delta}D910A/D910A CD4+CD25+Foxp3+ Tregs showed reduced ability to suppress the proliferation of CD4+CD25– T cells in vitro and failed to produce detectable levels of IL-10. In vivo, p110{delta}D910A/D910A T cells failed to protect against experimental colitis. We conclude that p110{delta} is dispensable for thymic development of Foxp3+ Tregs and yet plays a key role in Treg-mediated suppression of CD4+CD25– T cell proliferation and inflammation.


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

p110{delta}D910A/D910A mice (Pik3cdtm1.1Bvan) (18) (backcrossed to the C57BL/6 or BALB/c background for 8–10 generations) were examined between 6 and 12 wk of age along with age- and sex-matched control mice. Most experiments were repeated on both backgrounds with similar results. RAG1–/– mice (Rag1tm1Bal) (20) on the C57BL/10 background were kindly provided by Dr. A. Corcoran and Dr. F. Colucci (Babraham Institute). C57BL/6 and BALB/c mice were bred locally or purchased from Harlan Olac. All mice were maintained under specific pathogen-free conditions. All experiments were performed in accordance with U.K. Home Office regulations.

Reagents

All chemicals were purchased from Sigma-Aldrich or Invitrogen Life Technologies unless otherwise specified. All assays were performed in RPMI 1640 supplemented with 100 U/ml penicillin/streptomycin, 2 mM L-glutamine, 10 mM HEPES, 20 µM 2-ME, and 10% FCS. Recombinant human IL-2 was provided by GlaxoSmithKline.

Antibodies and flow cytometry

All mAbs were purchased from BD Biosciences or eBioscience, except for glucocorticoid-induced TNFR-PE (R&D Systems). Foxp3 expression was detected using the eBioscience Foxp3 staining kit according to the manufacturer’s instructions. Cells were stained with cell surface and intracellular markers as previously described (12, 18, 19). Cells were acquired with a BD Biosciences FACSCalibur instrument and analyzed using the CellQuest (BD Biosciences) or FlowJo (Tree Star) software packages.

Cell purification

T cells were purified from lymph nodes by magnetic sorting with beads from Miltenyi Biotech or Dynal. CD4+CD25– and CD4+CD25+ T cells were also isolated by the sorting of CD4+ T cells using a BD Biosciences FACSAria instrument. Spleen cells were depleted of T cells by staining with anti-Thy1.2 Ab (Sigma-Aldrich) followed by complement lysis using rabbit Lo-Tox-M serum (Cedarlane Laboratories). APCs were then recovered from the interface after centrifugation on Lympholyte-M (Cedarlane Laboratories).

CD4+CD25+ suppression assays

Purified CD4+CD25+ T cells (105/well) were cultured with CD25– T cells in the presence of Epoxy Dynabeads (Dynal) (one bead per five cells) coated with anti-CD3 and anti-CD28 mAbs or with anti-CD3-coated T cell-depleted spleen cells (APCs) in round-bottom 96-well plates. After 3 days, the incorporation of [3H]TdR was measured over 6 h or overnight. IL-10 was measured after 6 days using an ELISA (eBioscience). Recombinant human IL-2 was added at 20 ng/ml.

Colitis experiments

The capacity of p110{delta}D910A/D910A T cells to suppress colitis was tested by coinjecting purified wild-type (WT) or p110{delta}D910A/D910A CD4+CD25+ T cells (105 per mouse) with WT CD45RBhigh T cells (5 x 105 per mouse) into RAG1–/– recipients as described (21). The degree of colitis in each recipient was scored blind using histological sections of the colon prepared 8–9 wk after injection, according to the criteria published by Asseman et al. (21). Scores from representative slides of the cecum and the ascending and descending colons were averaged to give one score per mouse.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Treg development in p110{delta}D910A/D910A mice

Tregs can be identified by the expression of CD25 and Foxp3, the latter being considered a definitive lineage-specific marker (5, 6, 7, 8). As shown in Fig. 1A, CD25+Foxp3+ T cells were readily identified among the CD4+ T cell populations from the thymus, the peripheral lymph node (PLN), the mesenteric lymph nodes (MLN), and the spleen of WT and p110{delta}D910A/D910A mice. In both strains, the majority of CD25+ T cells coexpressed Foxp3 and vice versa as previously reported (7, 8). However, there was a 2-fold increase in the proportion of Tregs in the thymi of p110{delta}D910A/D910A mice, whereas in the peripheral lymphoid organs the proportions of Foxp3+ cells were decreased by 20–30% (Fig. 1B). The absolute numbers of Tregs followed a similar pattern, although in the PLNs and MLNs the absolute counts were more variable (Fig. 1C). Nonetheless, we consistently recovered about half as many Foxp3+ Tregs from p110{delta}D910A/D910A as from WT lymph nodes.


Figure 1
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  		FIGURE 1. Treg populations in p110{delta}D910A/D910A mice. Cells were stained with Abs for the cell surface markers CD4, CD8, and CD25 and for the intracellular marker Foxp3 and analyzed by flow cytometry. A, Expression of Foxp3 and CD25 in CD4+CD8– T cells from the thymus, PLN, MLN, and spleen from WT or p110{delta}D910A/D910A mice. B, The average percentage of CD4+ T cells expressing Foxp3 in the thymus (Thy), spleen (Spl), MLN, or PLN. C, The absolute numbers of Foxp3+ T cells recovered from the organs listed in A and B. In B and C, WT is represented by filled bars ({blacksquare}) and p110{delta}D910A/D910A by open bars ({square}). The percentages shown are the mean values from four individual mice. The error bars indicate the SD of the mean, and statistical significance is indicated as follows: *, p < 0.05; **, p < 0.005 (Student’s two-tailed t test).

 
In the thymus, the majority of Foxp3+ cells are known to be CD4+CD8–, but a small fraction of CD4+CD8+ and CD4–CD8+ T cells also express Foxp3 (7). In p110{delta}D910A/D910A mice, a ~2-fold increase in the proportion of Foxp3+ cells was observed in the mature CD4+CD8– subset as well as in the less mature CD4+CD8low subset, whereas in the CD4+CD8+ subset the proportions of Tregs were similar in WT and p110{delta}D910A/D910A mice (Fig. 2A). Because Treg development in the thymus is thought to be mediated by self-Ags (9, 10), we considered that the increased fraction of Tregs in the thymus of p110{delta}D910A/D910A mice could reflect a perturbation of the thymic selection process. Negative selection of autoreactive thymocytes occurs primarily in the thymic medulla during the transition from the double-positive stage to the single-positive stage of development (22). The relative increase in p110{delta}D910A/D910A Tregs in the immature CD4+CD8low fraction suggested that the appearance of Tregs may be linked with the process of negative selection. To investigate this process, we took advantage of the endogenous Mls superantigen (SAg) expressed in complex with the I-E MHC II molecule in BALB/c mice (23). T cells expressing Vbeta11 and Vbeta12 TCR, which bind the SAg-MHC complex, were less efficiently deleted in p110{delta}D910A/D910A than in WT mice as judged by their increased proportions in the thymus and the spleen (Fig. 2, B and C). The proportion of T cells bearing non-SAg binding Vbeta4 chains remains unaffected by the p110{delta}D910A/D910A mutation. These results suggest that negative selection is less efficient in p110{delta}-deficient thymocytes. Because p110{delta} is a positive regulator of TCR signaling, some self-ligands may stimulate a weaker signal in p110{delta}D910A/D910A mice, resulting in Treg development instead of thymocyte apoptosis.


Figure 2
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  		FIGURE 2. Developmental regulation of Foxp3 expression. Thymocyte subsets were analyzed for Foxp3 expression. A, The percentage of double-positive, CD4+CD8low, CD4+CD8–, CD4lowCD8+, and CD4–CD8+ T cells that express Foxp3 (n = 8). B and C, Expression of Vbeta4, Vbeta11, and Vbeta12 chains on CD4+ T cells in the thymus (B) and spleen (C), providing evidence for incomplete negative selection (n = 4). Error bars represent SD of the mean. *, p < 0.05; **, p < 0.01 (Student’s two-tailed t test).

 
IL-2 promotes proliferation of p110{delta}D910A/D910A Tregs

In the peripheral lymphoid organs, p110{delta}D910A/D910A Tregs were found to be less abundant but otherwise indistinguishable from WT Tregs based on staining with a panel of cell surface markers (data not shown). In particular, CTLA-4, which is thought to be important for Treg function (1, 24), was expressed similarly on WT and p110{delta}D910A/D910A Tregs.

Tregs have been considered anergic because they proliferate poorly in response to antigenic stimulation in vitro (1). Although neither WT nor p110{delta}D910A/D910A CD4+CD25+ T cells proliferated significantly in response to anti-CD3/CD28 stimulation, the addition of exogenous IL-2 stimulated both WT and p110{delta}D910A/D910A CD4+CD25+ T cells to proliferate robustly (Fig. 3A). Hence, p110{delta}D910A/D910A Tregs are viable and respond to anti-CD3 and anti-CD28 costimulation in the presence of exogenous IL-2.


Figure 3
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  		FIGURE 3. Impaired function of p110{delta}D910A/D910A CD4+CD25+ Tregs in vitro. A, Proliferation of CD4+CD25– and/or CD4+CD25+ T cells when stimulated with anti-CD3/CD28-coated beads in the presence or absence of IL-2. B, IL-10 produced by the T cells shown in A (detection limit, 155 pg/ml). C, Cocultures of WT or p110{delta}D910A/D910A CD4+CD25+ T cells mixed at ratios from 1:1 to 1:32 relative to WT CD4+CD25– T cells in the presence of anti-CD3/CD28-coated beads; proliferation was measured after 3 days. D, Coculture experiments as in C, but using APCs and anti-CD3 as stimulus. Error bars represent SEM of triplicate measurements. E, Prevention of colitis. RAG1–/– mice were injected with PBS (control) or with WT CD4+CD45RBhigh cells, either alone or with CD4+CD25+ T cells from WT or p110{delta}D910A/D910A mice. The colitis score was determined by histological analysis 8–9 wk after the injection. ** p < 0.005 (Student’s two-tailed t test).

 
Impaired IL-10 secretion by p110{delta}D910A/D910A Tregs

IL-2 has been shown to stimulate IL-10 production by activated Tregs (25). WT CD4+CD25+ and CD4+CD25– T cells produced large amounts of IL-10 upon stimulation with anti-CD3/CD28 in the presence of exogenous IL-2 (Fig. 3B). In contrast, no IL-10 was detected in the corresponding p110{delta}D910A/D910A cultures despite their increased proliferative response (Fig. 3A). Hence, whereas p110{delta} is dispensable for anti-CD3/CD28- and IL-2-driven proliferation of both CD4+CD25+ and CD4+CD25– T cells, p110{delta} is essential for IL-10 production by both T cell subsets.

Defective suppression by p110{delta}D910A/D910A CD4+CD25+ Tregs

To further examine the function of p110{delta}D910A/D910A Tregs, we established cocultures to examine the capacity of CD4+CD25+ T cells to suppress the proliferation of CD4+CD25– T cells that had been stimulated with anti-CD3- and anti-CD28-coated beads. WT CD4+CD25+ T cells suppressed proliferation in a dose-dependent manner (Fig. 3C). By contrast, p110{delta}D910A/D910A CD4+CD25+ T cells failed to suppress WT or p110{delta}D910A/D910A responder cells at any ratio tested. When anti-CD3-coated APCs were used as stimulus, the p110{delta}D910A/D910A T cells showed suppressive capacity but were ~50% less effective than WT Tregs (Fig. 3D). The reason underlying the difference in suppressive capacity between these two assays is unclear, but these results demonstrate that, on a per cell basis, p110{delta}D910A/D910A Tregs are functionally compromised in vitro, the severity of this defect depending on the method of activation of the Tregs and/or responder cells.

To determine whether p110{delta}D910A/D910A Tregs were functional in vivo, we conducted experiments in which Tregs offer protection from colitis caused by the transfer of CD4+CD45RBhigh cells into RAG1–/– recipients (21). WT Tregs suppressed the capacity of CD45RBhigh T cells to cause colitis, as determined by histological examination of the colon 8–9 wk after transfer (Fig. 3E). In contrast, mice coinjected with p110{delta}D910A/D910A Tregs developed colitis that was indistinguishable from that in mice injected with CD4+CD45RBhigh cells alone.

The precise mechanism of Treg-mediated suppression of T cell proliferation is not known, but is thought to be contact-dependent and cytokine-independent in vitro (1, 26, 27). Consistent with this notion, the addition of anti-IL-10 or anti-TGF-beta did not affect the capacity of WT Tregs to suppress proliferation (data not shown). Tregs need to be activated themselves before they can suppress T cell proliferation. The defective suppression by p110{delta}D910A/D910A Tregs is unlikely to be a consequence of deficiencies in IL-2R or CD28 signaling; CD28 is required for the development but not the function, of Tregs (24, 28), and IL-2 is required to maintain peripheral homeostasis of Tregs but not for in vitro suppression (13, 14). Our data therefore suggest a specific role for p110{delta} in TCR-dependent modulation of Treg-mediated suppression, perhaps by the induction of an inhibitory protein or another positive regulator of Treg function. Foxp3-deficient mice develop a lethal autoimmune syndrome as a consequence of deficient suppression of Th cells (4, 5, 6). The absence of lethal autoimmunity in p110{delta}D910A/D910A mice suggests that some suppressive capacity is retained in the absence of p110{delta} activity, as evidenced by Fig. 3D. In addition, defective Th1 and Th2 cell clonal expansion and differentiation in p110{delta}D910A/D910A mice (19) may help to protect them from autoimmune manifestations that would otherwise occur in a Th cell-sufficient host.


   Acknowledgments
 
We thank Juliet Emery and Adam Hales for expert technical assistance and animal husbandry. We are also grateful to Martin Turner and Francesco Colucci for constructive comments on this manuscript. Individual author contributions are as follows: D.T.P., O.A.G., L.S.K.W., B.V., and K.O. designed the research; D.T.P., O.A.G., L.E.C., C.R.M., E.L., and K.O. conducted the research; W.P.P. and S.S. prepared and scored the colon sections; L.E.C. and L.S.K.W. analyzed the Treg phenotypic markers; D.T.P., O.A.G., W.C.R., L.S.K.W. and KO analyzed data; and O.A.G. and K.O. wrote 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 O.A.G. was supported by a Wellcome Trust Advanced Fellowship. D.T.P. and C.R.M. were supported by Medical Research Council PhD studentships. D.T.P. was also supported by a Collaborative Award in Science and Engineering (CASE) contribution from GlaxoSmithKline. L.C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC)/AstraZeneca CASE studentship. L.S.K.W. was supported by an Medical Research Council Career Development Fellowship. W.P.P. was supported by the Migration and Inflammation Framework VI consortium. B.V. was supported by the Ludwig Institute for Cancer Research. K.O. was supported by a BBSRC David Phillips Fellowship. Back

2 D.T.P. and O.A.G. made equal contributions to this manuscript. Back

3 Address correspondence and reprint requests to Dr. Klaus Okkenhaug, Laboratory of Lymphocyte Signalling and Development, Babraham Institute, CB2 4AT Cambridge, United Kingdom. E-mail address: klaus.okkenhaug{at}bbsrc.ac.uk or Dr. Oliver Garden, Regulatory T Cell Laboratory, Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, United Kingdom or Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, United Kingdom. E-mail address: o.garden{at}imperial.ac.uk or ogarden{at}rvc.ac.uk Back

4 Abbreviations used in this paper: Treg, regulatory T cell; PLN, peripheral lymph node; MLN, mesenteric lymph node; WT, wild type; SAg, superantigen. Back

Received for publication March 14, 2006. Accepted for publication September 8, 2006.


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

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