The control of CD4+CD25+Foxp3+regulatory T cell survival
© Pandiyan and Lenardo; licensee BioMed Central Ltd. 2008
Received: 19 February 2008
Accepted: 27 February 2008
Published: 27 February 2008
CD4+CD25+Foxp3+ regulatory T (Treg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that Treg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of Treg cells in Bim-/- and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25+ cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in Treg cells. Our study reveals that the survival of Treg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate Treg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate Treg cells that could be utilized for their therapeutic applications.
This article was reviewed by: Avinash Bhandoola, Fred Ramsdell (nominated by Juan Carlos Zuniga-Pflucker) and Anne Cooke.
CD4+CD25+Foxp3+ Treg cells are a subset of lymphocytes having an anergic phenotype as shown by their absence of proliferation and production of IL-2 upon TCR stimulation. [1, 2] They have been shown to suppress various inflammatory and autoimmune responses in mice and humans. Absence of this population of T cells causes an acute autoimmune condition called Immune dysregulation Polyendocrinopathy Enteropathy X-linked syndrome (IPEX) in humans and fatal autoimmune manifestations in mice [3–7]. Treg cells cause cytokine deprivation death by consuming cytokines from CD4 T cells to cause suppressive apoptosis. This is probably one of the default mechanisms of how Treg cells operate in the close vicinity of CD4 T cells . Evidence show that self-peptides are important for homeostatic expansion of Treg cells in the periphery . Despite the abundant availability of self-peptides, the frequency of Treg cells is always 10–15% of CD4+ population. Increase or decrease in Treg numbers would result in immune imbalance as evidenced by suppressive effects of Treg cells on other immune cells. However, parameters controlling Treg cells and their survival maintaining the normal Treg numbers in vivo, remain unclear [10, 11]. FAS and TCR restimulation mediated death constitute two of the major mechanisms regulating T cell survival and homeostasis [12–14]. However, Treg cells are shown to be resistant to these active forms of death [15, 16]. IL-2 is shown to be a major survival factor of Treg cells, but the role of other cytokines is unknown. One study proposes the role of gamma chain cytokines in regulating the suppressive potential of human Treg cells . However, the direct contribution of these cytokines in the survival of Treg cells remains undocumented. Exploiting Treg cells for therapeutical applications demands a complete understanding of their survival mechanisms in vitro and in vivo. Here we show evidence that common γ chain cytokines play a major role in Treg survival in the periphery.
Common chain (γc) cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, bind to multimeric receptors that share the common γ chain (γc) [19–26]. Common γc is a critical part of the cytokine receptors that confers the ability of as γc cytokines to activate MAP kinase and PI3 kinase signaling, leading to anti-apoptotic and proliferation signals in lymphocytes [24, 27]. For example, IL-2 binds to IL-2R complex consisting of IL-2R-α, which possesses a short cytoplasmic domain. IL-2R-α binds IL-2 only with low affinity and does not recruit intra cytoplasmic signaling molecules. β chain (IL-2/15Rβ), shared by the IL-15 receptor stimulates downstream signaling pathways. However, γc is the most crucial component of the IL-2 receptor complex, raising its binding affinity for IL-2 and thus initiating a potent IL-2 signaling . γc chain cytokines are pleiotropic soluble factors crucial for lymphocyte generation, survival and homeostasis . Defects in γc signaling components result in impaired B, T, and natural killer (NK) cell development, leading to severe combined immunodeficiency in humans and mice [30, 31]. The roles of IL-7 and IL-15 in the homeostasis of naïve CD4 and memory CD8 cells respectively, are well documented [21, 24, 32, 33]. The importance of IL-2 in lymphocyte homeostasis is shown by a severe autoimmunity in mice deficient in IL-2 signaling components [34, 35]. The autoimmune phenotype observed in these mice has been attributed to the loss of cell death mechanism mediated by FAS and absence of Treg cells in these mice [36, 37]. Besides maintaining the homeostasis of naïve and memory cells, γc-cytokine signaling plays an important role during differentiation of activated T cells in vivo . How γc-cytokines impact Treg cells in vivo is not well studied. The absence of Treg cells in γc-knockout mice seems to suggest that the common gamma chain signaling is important for the development of Treg cells. However, whether these cytokines influence the peripheral survival and expansion of Treg cells is not known. Here we show that gamma chain cytokines are crucial for maintaining the Treg cells in the periphery without which they undergo apoptosis.
BALB/c, C57BL/6, Bim-/- mice and Scurfy mice were purchased from Jackson Laboratories. 129 Foxp3-eGFP transgenic mice were purchased from Taconic farms. CB-17 scid mice were also purchased from Charles River Laboratories. All mice were maintained in NIAID animal facility and cared for in accordance with institutional guidelines.
Reagents and antibodies
Purified anti-CD3 (145-2C11), purified anti-CD28 (37.51), anti-CD25 (3C7), biotin-conjugated anti-CD25 (7D4), fluorescein isothiocyanate-conjugated anti-CD4 (GK1.5), phycoerythrin-conjugated anti-CD25 (PC61), unconjugated, allophycocyanin- or phycoerythrin-conjugated anti-IL-2 (JES6-5H4), anti-IL-4 (11B11) and anti-IL-4Rα (mIL4R-M1) are from BD Biosciences. Anti-Foxp3 (FJK-16S) and anti-IL-7Rα (A7R34) are from eBiosciences. The anti-FITC Multisort kit, IL-2 secretion assay kit and anti-biotin microbeads were from Miltenyi Biotec. The IL-2 Quantikine enzyme-linked immunosorbent assay (ELISA) kit and recombinant mouse IL-2, IL-7, IL-4, IL-15 and IL-21 were purchased from R&D Systems. Cell cultures were performed in complete RPMI 1640 medium (Bio-Whittaker) supplemented with 10% (vol/vol) FCS, 100 U/ml of penicillin, 100 μg/ml of streptomycin, 2 mM glutamine, 10 mM HEPES, 1 mM sodium pyruvate and 50 μM β-mercaptoethanol.
Splenocytes were harvested from 5 to 12 week old mice. Erythrocytes were osmotically-lysed using Ack lysing buffer (Bio Whitaker) and single cell suspensions were incubated with FITC-conjugated anti-CD4 and biotin-conjugated anti-CD25 followed by incubation with anti-FITC microbeads. CD4+ T cells were then purified by magnetic isolation using the Auto MACS sorter (Miltenyi Biotec). For isolation of CD4+CD25+ Treg cells, after releasing the beads, the purified CD4+ T cell suspension was incubated with α-biotin microbeads followed by separation using the Auto MACS. In all the experiments 90 to 95% of these cells were positive for CD4 and CD25. The negative fractions were depleted of CD25+ cells to obtain CD4+CD25- cells.
T cell death and co-culture assays
Tcon cells (6 × 104) or Treg were cultured in U-bottom 96-well plates in the presence of soluble 0.75 μg/ml α-CD3 and 3 μg/ml α-CD28 for 3–4 days. Death was measured by flow cytometry after 3 days. For co-culture assays, CD4+CD25- responder T cells (Tresp) (3 × 104) were cultured in U-bottom 96-well plates with Tcon (CD4+CD25-) (3 × 104) or Treg (CD4+CD25+) in the presence of soluble 0.5–0.75 μg/ml α-CD3 and 3–4 μg/ml α-CD28 for 2–4 days. Treg or Tcon cells were used in the co-culture with responders directly in U-bottom 96-well plates. Tresp cells were CFSE-labeled to distinguish them from Tcon or Treg cells in co-culture. Proliferation was also assayed by CFSE dilution. Cell death analyses of CFSE+ responders were performed based on forward scatter and propidium iodide staining. All flow cytometry analyses assessing cell death were performed with events acquired at constant time, in order to count the events. The percentage of survival (Survival (%)) in all analyses is the percentage of cells that FSChigh and PI-. When indicated, IL-2 (1000 U/ml), IL-7 (20 ng/ml), IL-4 (20 ng/ml), IL-15 (20 ng/ml), IL-21 (20 ng/ml) was added. For IL-2 blocking experiments, CD4+CD25- cells were isolated and 6 × 104 cells were stimulated with anti-CD3 and anti-CD28 in the presence of isotype control or cytokine blocking antibodies, 10 μg/ml each, and cultured in 96-well U-bottomed plate.
Tcon or Treg cells isolated from cultures were washed with PBS twice, fixed with fixation buffer containing Glutaraldehyde and Sodium Cacodylate. Fixed cells were pelleted and sent to electron microscopy facility at SAIC-Frederick, Inc. for imaging and analyses.
Results and Discussion
Gamma chain cytokines are essential for the survival of Treg cells in vitro
Treg cells express cytokine receptors in vitro
Treg cells die due to cytokine deprivation in vivo
Gamma chain cytokines maintain CD25 and Foxp3 expression in Tregcells
Foxp3 dictates the cytokine dependence in Tregcells
Taken together, our data have important implications in the understanding of behavior and regulation of Treg cells. Here, we demonstrate that Treg cells are highly susceptible to apoptosis in the absence of cytokines. This cytokine withdrawal apoptosis in Treg cells is substantially abolished by the γc cytokines in vitro. Our data also reveal that Bim-/- mice accumulate higher frequencies of Treg cells showing the importance of cytokine withdrawal death in regulating peripheral Treg cells. Moreover, Treg cells from Bim-/- mice do not depend on cytokines for survival in vitro. In addition to enhancing their survival, the γc cytokines also maintain CD25 and Foxp3 expression in Treg cells, thus maintaining their suppressive potential. Most importantly, our data show that Foxp3 appears to confer the inability to produce cytokines in Treg cells thus increasing their dependence to extra-cellular sources of cytokines for survival and function. We have described here a cytokine dependent homeostatic regulation mechanism of the Treg cells. Along with the self-peptides, the availability of γc cytokines probably keeps the Treg numbers in constant check thus maintaining both protective and regulatory arms of the immune system in balance. Thus, our study highlights the important role of γc cytokines in regulating Treg survival, opening new ways to manipulate Treg cells.
Reviewer's report 1
Dr Avinash Bhandoola, University of Pennsylvania School of Medicine, Philadelphia
PA United States
I thought there was plenty of interesting new data in this work. I have a few very minor comments that should be simple to deal with, and do not need to be published. 1) I thought the abstract somewhat repetitious in places. It could be shortened. 2) The figure legends do not clearly explain 3b, particularly the bottom 2 panels. 3) I did not understand the relevance of the right-most panels in Fig. 3g (WT or Bim-/- Treg + IL-7), particularly when compared to the two preceding panels (WT or Bim-/- Treg). Is it referred to at all in the text, or otherwise explained?
Relevant changes are made in the abstract and more clarifications are included in the figure legends according to reviewer's comments.
Reviewer's report 2
Fred Ramsdell, Associate Director, Zymogenetics, Seattle, WA 98102
Overall, the manuscript is well-written and concise. The connection between g-c receptor signaling and apoptosis – and the distinction between these cytokines and proliferation – is a significant finding and generally well supported by the data. To date, the bulk of studies on Treg survival/activity and cytokines has focused on IL-2, and the extension to other gamma-c receptor using cytokines provides a more comprehensive analysis of this biology.
Whilst the experiments in Fig 5 are an interesting attempt to address the function of Foxp3 with respect to cytokine dependence, the conclusions are not fully supported by the data. The abstract states that in scurfy mice, "Foxp3 increases their (CD25+ cells) dependence on cytokines by suppressing cytokine production in Treg cells." Whilst Foxp3 does appear to directly suppress cytokine production, it does so in any T cell and the major effect of lack of Foxp3 in scurfy mice would appear to be the absence of the TR lineage more broadly. Thus, this is not an appropriate way to test "whether Foxp3 is important in Treg cells for the extreme cytokine dependence for their survival" as these mice don't have Treg cells. Previous data has demonstrated that scurfy T cells do not express Foxp3, that they are CD25+ and that these cells do not have any Treg activity (Khattri, et. al.). In fact, these cells produce large amounts of IL-2 and many other cytokines. Importantly however, the cells remaining in scurfy mice do not appear to be in any way related to Treg cells. The data in the manuscript is consistent with data from Foxp3 transgenic mice in which Foxp3 levels are increased, but the actual number of Treg cells is decreased, as are their CD25 levels – perhaps due to Foxp3 inhibition of g-c derived (IL2 or other) secretion. This figure however does not seem necessary to me for the manuscript to be of interest.
This data indicates that not all CD25 + cells consume and depend on cytokine in vitro. In the absence of Foxp3 in Scurfy mice, CD25 + cells do not depend on IL-2 and other cytokines and make cytokines themselves. Even though our data do not show that Foxp3 determines cytokine dependence directly, we feel that there is a strong implication that the presence of Foxp3 inversely correlates with cytokine production in Treg cells, based on the fact that Foxp3 expression is restricted to Treg cells in mice. The weakness in this experiment, and a point on which we agree with the reviewer, is that it is not clear that the CD25-expressing cells in the Scurfy mice are related to CD25-expressing Treg cells in WT mice. For example, if Treg cells are truly absent in Scurfy animals, then the CD25-expressing T cells could be from a completely different lineage of CD4+ T cells. In this case, we would be comparing different lineages and the results would not indicate a direct effect of FoxP3. Alternatively, it might be that the FoxP3-negative, CD25-expressing cells in Scurfy mice are cells that would otherwise would have become Tregs, then our data gives a better insight into the role of FoxP3. In either case, a cleaner experiment would be to perform a knockdown of FoxP3 in WT mouse Tregs and assess if they now produce cytokines at a normal level and are no longer susceptible to apoptosis in the absence of exogenous cytokines. We are working on executing this experiment in the future. However, the results in Fig. 5show that Foxp3 expression and function but not expression of cytokine receptors alone determines cytokine consumption. Sakaguchi and colleagues (Hori et al, 2003, Science) have shown that Foxp3 transduction alone converts normal T cell in to a Treg cell validating our finding that the function of Foxp3 is restricted to Treg cell. Therefore, we feel that Fig. 5 is necessary for the manuscript.
One further observation is that it appears to be very clear in Fig 3a/b that the amount of Foxp3 protein is substantially less in the Bcl-2 tg and Bim -/- Treg cells than in conventional cells (although this is less evident in Fig 4). Previous data has suggested that the absolute amount of Foxp3 can be a critical factor in regulating the amount of suppressive activity by Treg cells, and the functional data in Fig 4e/f would support this. But I am unclear why, in the model proposed, there might be less Foxp3 protein in cells from these animals and I would be interested to hear the author's speculation on this.
We speculate that Treg cells in Bcl-2 tg and Bim-/- mice, do not die even when cytokine levels are less abundant resulting in accumulation of T reg cells. Therefore, the available cytokines are being shared by more T reg cells. Each T reg cell could potentially be exposed to lower amounts of cytokines, which possibly results in Foxp3 downregulation (because cytokines maintain Foxp3 expression).
Some minor points for consideration
Although correct as written, it might be more informative to indicate in the abstract that ANY g-c using cytokine protects Treg cells from apoptosis – although only IL2 appears to be capable of inducing proliferation. This distinction is one of the more salient features of the article. It seems appropriate to reference the work of Malek and colleagues (particularly Bayer, Yu and Malek, JI, 2007) when referring to previous studies on the role of IL-2 and Treg development (eg, in reference to Fig 1). In Figure 2, for panels e-g, please clarify the conditions for the upper versus lower histograms (presumably resting versus activated). I declare that I have no competing interests.
The abstract has been rewritten reiterating the differential effects of gamma chain cytokines on survival and proliferation. The Figure. 2 legend has been modified and the Malek reference is included as suggested by the reviewer.
Reviewer's report 3
Anne Cooke, University of Cambridge, Department of Pathology, Tennis Court Rd
Cambridge, CB21QP, United Kingdom
In this manuscript the authors have examined the role of common gamma chain (γc) cytokines in CD4+ CD25+ Foxp3+ T cell survival. They clearly show that cytokines other than IL-2 that signal through the γc prevent apoptosis of T reg cells following stimulation with αCD3 and αCD28. This provides a nice explanation for the presence of T reg in CD25 deficient mice. While addition of exogenous γc cytokines enabled T reg survival, they are proposed individually not to be as effective as IL-2. This reviewer was unclear whether all the cytokines had been titrated to determine efficacy. Were the cytokines titrated fully and were doses greater than 20 ng/ml used?
All cytokines were used at 20 ng/ml, which is an excessive amount in culture of 60,000 cells based on established biologically active concentrations.
The link to apoptosis in Treg survival was nicely further substantiated by studies using T reg from Bcl-2 transgenic or BIM deficient mice. It appeared that there was some induction of Foxp3 expression in responding cells co-cultured with Treg. Was this TGFβ and/or cell contact dependent? The authors do not comment on the ability of IL-7 to reverse this.
We did not test if the induction of Foxp3 in T resp cells was TGF-β dependent as it was not the focus of the current study. It is an interesting experiment for the future and we appreciate this suggestion. However, in the presence of T reg cells and IL-7, the frequency of induced Foxp3+ cells seems to be diminished, probably due to an increased proliferation of non Foxp3 + CD4 + T resp cells as compared to induced Foxp3 + CD4 + T resp cells in the presence of IL-7. We have included this comment in the last sentence of the relevant paragraph in the results section.
The final observation that Foxp3 expression suppresses cytokine production in T reg cells is interesting and in line with the studies of others. It was somewhat surprising that the work of others was not mentioned and the data from this current submission not situated in the context of the studies by Sakaguchi and his colleagues (Ono et al (2007) Nature 446:685–689.) showing Runx1 interaction with FoxP3 and inhibition of IL-2 gene transcription as well as others. Rao and colleagues (Wu et al Cell 2006) had also previously predicted an effect of FoxP3/NFAT interaction on the transcription of several genes including IL-2. The manuscript would have been improved by including some discussion of these.
References and discussion are included as per the suggestions of the reviewer.
The authors thank Lixin Zheng, Carol Trageser and other members of the Lenardo laboratory for discussion and help. We thank Owen Schwartz and Meggan Czapiga for their help in confocal microscopy and Kunio Nagashima for assistance in electron microscopy. This work was supported by the intramural research program of NIAID, NIH. P.P is supported by a National Academy of Sciences/National Research Council fellowship.
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