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* Dipartimento di Medicina Interna, Università Tor Vergata, Rome, Italy;
Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanita’, Rome, Italy; and
Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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-chain of the IL-2 and IL-15 receptors and interacts with the common 
cytokine receptor chain (1). Studies both in humans and mice have shown that IL-21 can enhance the growth and functional activity of T, B, and NK cells (1, 2). In line with this, enhanced expression of IL-21 and/or IL-21R has been documented in inflammatory diseases (3, 4, 5). Moreover, mice overexpressing IL-21 exhibit inflammatory infiltrates in several tissues (6), thus raising the possibility that IL-21 may play an important role in the induction and/or perpetuation of immune-inflammatory processes. In contrast, IL-21 exerts antitumor effects in vivo (1, 7), suggesting that this cytokine may have therapeutic potential. Recent studies have led to the identification of a subpopulation of CD4+CD25+ T lymphocytes, termed regulatory T cells (Treg),3 that specifically express the forkhead transcription factor, forkhead winged-helix transcription factor gene (Foxp3) (8). Treg have important effects on the adaptive immune system but in a direction opposing that of IL-21. Indeed, Treg are highly specialized for the suppression of proliferation of autoreactive and effector T cells and therefore in the maintenance of immune homeostasis (8, 9). This function is further substantiated by the demonstration that the loss of Foxp3 results in a fatal autoimmune disorder (8, 9). Consistently, a decreased number and/or defective activity of Treg has been documented in autoimmune and allergic diseases (10). In contrast, Treg may sabotage effective immune responses against microbes and tumors (7, 8).
In addition to naturally occurring Treg that are produced by the thymus as a functionally distinct and mature population of T cells, Treg can arise in the periphery upon conversion of CD4+CD25– T cells into Foxp3+CD4+CD25+ cells in response to a variety of stimuli (8, 11), thus raising the possibility that the development and/or suppressor activity of Treg can be regulated. Indeed, recent studies have shown that molecules produced by inflammatory and tumor cells can either inhibit or enhance Treg function (12, 13). As IL-21 and Treg have opposite effects on CD4+ T cell activation, we hypothesized that IL-21 can make conventional CD4+CD25– T cells able to escape Treg-mediated suppression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Human PBMC were isolated from enriched buffy coats of healthy volunteer donors and used to purify CD4+ T cells with the CD4 multisort magnetic microbeads kit (Miltenyi Biotec). The remaining CD4– fraction of PBMC was then used to purify CD8+ T cells by using CD8 multisort magnetic beads (Miltenyi Biotec). Both CD4+ and CD8+ T cells were subsequently fractioned in CD25+ and CD25– cells by using CD25 magnetic beads (Miltenyi Biotec). In some experiments, CD3+ T cells were purified from enriched buffy coats using the CD3 magnetic beads (Miltenyi Biotec). Cell purity was routinely evaluated by flow cytometry and ranged between 96 and 98%. The study received approval from the local ethical committee.
Responder cells (CD4+CD25– T cells, CD8+CD25– T cells, or CD3+ T cells) were cultured in RPMI 1640 containing 10% FBS and standard supplements (all from Sigma-Aldrich) in 96 U-bottom multiwells (5 x 104 cells/well/200 µl) in the presence or absence of activating anti-CD3-bound beads (final concentration of 5 x 104 beads/well/200 µl) according to the manufacturer’s instructions (Miltenyi Biotec). In parallel, cell cultures were added with graded doses of IL-21 (50–200 ng/ml; BioSource International). For suppression experiments, CD4+CD25–, CD8+CD25–, or CD3+ T cells (5 x 104 cells/well/200 µl) were cultured as indicated above in the presence of various concentrations of CD4+CD25+ cells (1.25, 2.5, and 5 x 104 cells/well/200 µl). Cocultures were either left unstimulated or stimulated with activating CD3 beads in the presence or absence of IL-21 (50–200 ng/ml), IL-2 (100 ng/ml; R&D Systems), IL-7 (100 ng/ml), or IL-15 (100 ng/ml; both from PeproTech). When suppression experiments were performed using CD3+ T cells as responder cells, the proliferation of both CD8+ and CD4+ T cells was evaluated by staining the cells with anti-CD8-allophycocyanin Ab. To evaluate whether Treg suppress the growth of responder cells when added late into the culture, CD4+CD25– T cells were stimulated with anti-CD3, and CD4+CD25+T cells (1:1) were added at the same time or 24 h after the activation of CD4+CD25– T cells.
In parallel experiments, cocultures of CD4+CD25+ T cells and CD4+CD25– T cells were performed as indicated above in the presence of anti-CD3 for 0, 12, 24, and 48 h, followed by the addition of 100 ng/ml IL-21.
To examine whether the pretreatment of Treg with IL-21 altered the suppressive capability of these cells, CD4+CD25– T cells (5 x 104 cells/well/200 µl) were stimulated with activating CD3 and CD28 beads (both used at a final concentration of 5 x 104 beads/well/200 µl; Miltenyi Biotec) to enhance the percentage of Treg in vitro. These cell cultures were or were not added to 100 ng/ml IL-21. After 5 days of culture, an aliquot of cells was used for analysis of CD25 and Foxp3, whereas the remaining cells were extensively washed and then tested for their ability to inhibit alloresponses. For this purpose, Treg (5 x 104 cells/well/200 µl) generated either in the presence or absence of IL-21 (10 x 104 cells/well/200 µl) were cocultured with allogenic CFSE-labeled CD4+CD25– T cells in the presence of activating CD3 beads. Cell proliferation was evaluated at the indicated time points.
CFSE labeling
To track the proliferation of responder cells, CD4+CD25–, CD8+CD25–, or CD3+ T cells were incubated in 0.2 µM CFSE (Invitrogen Life Technologies) at 37°C for 30 min, and CD4+CD25+ T cells were either left unlabeled or labeled with 2 µM PKH26 (Sigma-Aldrich) at room temperature for 3 min and extensively washed before culture. In some experiments, responder cells were labeled with PKH26 and CD4+CD25+ T cells were labeled with CFSE. CFSE fluorescence was evaluated with the FL1 detector and PKH26 with the FL2 detector. Flow cytometric data were analyzed with the proliferation Wizard module in ModFit LT Macintosh software. The proportion of cells undergoing divisions was determined.
Annexin V (Ann V) staining
To evaluate whether IL-21 affects the survival of CD4+CD25+ T cells, this cell type was cultured either alone or with CD4+CD25– T cells in the presence of anti-CD3 and/or IL-21. In these cocultures, CD4+CD25– T cells were labeled with CFSE. After 1, 2, 3, and 5 days of culture, the fraction of Ann V+ cells was evaluated by flow cytometry using a commercially available kit (Beckman Coulter).
Cell phenotype analysis
Anti-CD4 FITC, anti-CD8 allophycocyanin, anti-CD25 PE (all from Beckman Coulter), anti-CD3 PerCP (BD Biosciences), anti-IL-21R PE (DBA Italia), anti-Foxp3 allophycocyanin (Società Chimici Italiana), and control isotype Abs were used for analysis of relative Ags at the indicated time points according to the manufacturer’s instructions.
Cytokine assays
At the end of the cell culture, supernatants were collected and analyzed for the content of IFN- by ELISA using a commercially available kit (R&D Systems).
Statistics
Two-way ANOVA, followed by pairwise multiple comparison procedures (Student-Newman-Keuls method), were performed. Data are expressed as mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Since inflammatory stimuli block the ability of Treg to inhibit T cell activation (12, 14), we assessed whether IL-21 could alter Treg-mediated immunosuppression. We first examined the proliferative effect of IL-21 on purified CFSE-labeled CD4+CD25– T cells. The addition of IL-21 to CD4+CD25– T cell cultures resulted in no change in cell growth (Fig. 1A). In contrast, IL-21 enhanced the proliferation of anti-CD3-stimulated CD4+CD25– T cells (Fig. 1, A and B). The IL-21-induced mitogenic effect was dose dependent, with significant proliferation seen at 100 ng/ml IL-21 (p < 0.001; Fig. 1A), a concentration similar to that used by other authors to assess the biological activities of IL-21 in vitro (5). We have also attempted to examine the effect of IL-21 on purified CD4+CD25+ T cells with no CD4+CD25– T cells in the culture. However, in the absence of CD4+CD25– T cells, >50 and 80% of CD4+CD25+ T cells underwent apoptosis by 24 and 72 h of culture, respectively, regardless of whether cells were stimulated with anti-CD3 or anti-CD3 plus IL-21.
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Consistent with the above data, we also showed that the addition of IL-21 to cocultures of CD4+CD25– and CD4+CD25+ T cells prevented the inhibition of IFN- secretion (Fig. 1D).
Analysis of the kinetics of Treg activity in vitro has revealed that murine CD4+CD25+ T cells mediate their suppressive activity within the first 12 h of T cell activation, and that responding T cells become refractory to suppression if Treg are added 12 h after the activation of target cells (15). To examine whether this occurs also with human cells, CD4+CD25+T cells were added at the same time or 24 h after the activation of CFSE-labeled CD4+CD25– T cells. As expected, CD4+CD25+ T cells significantly inhibited the proliferation of anti-CD3-stimulated CD4+CD25– T cells when these two cell types were cocultured simultaneously. In contrast, no inhibitory effect was seen when CD4+CD25+ T cells were added 24 h after the activation of responder cells (Fig. 2A). Subsequently, we evaluated whether IL-21 exerts its effects in already established cocultures of responders and Treg. To this end, IL-21 was added 0, 12, 24, and 48 h after the anti-CD3 activation of cocultures of CFSE-labeled CD4+CD25– and CD4+CD25+ T cells. Data in Fig. 2B show that IL-21 was able to significantly counteract the suppressive effect of CD4+CD25+ T cells on CD4+CD25– T cell proliferation when added at the same time or 12 or 24 h after the activation of the cocultures. By contrast, IL-21 did partially, but not significantly, block the CD4+CD25+T cell-mediated suppression of CD4+CD25– T cell growth if it was added 48 h after the activation of CD4+CD25– T cells (Fig. 2B).
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The above results suggest different mechanisms by which IL-21 could exert its effects in the cocultures of responder and Treg cells. First, IL-21 could promote Treg apoptosis. Second, IL-21 could directly antagonize the Treg activity. Third, IL-21 could make responder T cells resistant to Treg-mediated suppression. Finally, IL-21 could enable responder cells to resist the antiproliferative activity of Treg, leaving other functions of responder cells compromised. To begin to address this issue, we first assessed which cells express IL-21R. Two-color immunofluorescence revealed that IL-21R expression ranged from 0.5 to 8% in freshly isolated CD4+CD25+ T cells. However, the simultaneous evaluation of Foxp3 and IL-21R in these cells revealed that the receptor was undetectable in freshly isolated Treg (Fig. 3A). Moreover, IL-21R was barely detectable in CD4+CD25– T cells (Fig. 3A). We also examined whether IL-21R was differently modulated in cocultures of CD4+CD25+ and CD4+CD25– T cells. As indicated above, the two cell populations were clearly distinguishable because CD4+CD25– T cells were labeled with CFSE. In anti-CD3-stimulated cocultures, 45 ± 10% of CD4+CD25– and 60 ± 10% of CD4+CD25+ T cells were positive for IL-21R. The addition of IL-21 to the cocultures did not increase the expression of IL-21R in CD4+CD25+ T cells (60 ± 5%), although it increased expression in CD4+CD25– T cells (63 ± 7%, p = 0.034). Moreover, CFSE dilutions revealed that proliferating CD4+CD25– T cells in culture with IL-21 expressed the IL-21R (Fig. 3B).
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IL-21 enhances CD8+ T cell growth but does not counteract the Treg-mediated suppression of CD8+ T cell proliferation
Because it is known that Treg abrogate the proliferation of CD8+ T cells (18), we then examined whether IL-21 also counteracts CD4+CD25+ T cell-mediated inhibition of CD8+ T cell growth. Initially, we evaluated the expression of IL-21R on freshly isolated CD8+ T cells. IL-21R was, however, barely detectable on these cells. We also examined whether IL-21R expression on CD8+CD25– T cells was modified in cocultures with CD4+CD25+ T cells by anti-CD3 and/or IL-21. To distinguish the two cell types, CD8+CD25– T cells were labeled with CFSE. In anti-CD3-stimulated cocultures, 41 ± 11% of CD8+ T cells were positive for IL-21R, and such an expression was not significantly affected by IL-21 (39 ± 9%; Fig. 6A). Subsequently, we evaluated whether IL-21 blocked the CD4+CD25+ T cell-mediated suppression of CD8+CD25– T cell growth. For this purpose, freshly isolated, CFSE-labeled, CD8+CD25– T cells were cultured with or without CD4+CD25+ T cells (1:1 final ratio), and the cultures were then stimulated with anti-CD3 in the presence or absence of IL-21 for 5 days. As observed with CD4+CD25– T cells, the addition of IL-21 to cultures of CD8+CD25– T cells did not enhance the cell growth (Fig. 6B). However, IL-21 significantly augmented the proliferation of anti-CD3-activated CD8+CD25– T cells at doses of 100 and 200 ng/ml (Fig. 6B; p < 0.05). The addition of CD4+CD25+ T cells to anti-CD3-activated CD8+CD25– T cell cultures resulted in a marked suppression of CD8+ T cell growth regardless of whether cocultures were performed in the presence or absence of IL-21 (Fig. 6, B and C; p < 0.05).
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IL-21, IL-2, IL-7, and IL-15 differ in their ability to overcome the CD4+CD25+ T cell-mediated immunosuppression
Studies in other systems have shown that the block of the Treg-induced immunosuppression by activating molecules, such as IL-2, IL-7, and IL-15, associates with the ability of these stimuli to reverse the anergic phenotype of suppressors (19, 20). We therefore compared the effect of IL-21 and the other common -chain-related cytokines on the proliferation of both CD4+CD25– and CD4+CD25+ T cells. Freshly isolated CD4+CD25– and CD4+CD25+ T cells were labeled with CFSE and PKH26, respectively, and then cocultured in medium containing anti-CD3 in the presence or absence of IL-21 (100 ng/ml), IL-2 (100 ng/ml), IL-7 (100 ng/ml), or IL-15 (100 ng/ml) for 5 days. Data in Fig. 7A show that all of these cytokines were effective in counteracting the CD4+CD25+ T cell-mediated suppression of anti-CD3-activated CD4+CD25– T cells (p < 0.01), even though the proliferative effect of IL-2, IL-7, and IL-15 on CD4+CD25– T cells was more marked than that of IL-21. By contrast, in the same cell cultures, IL-2, IL-7, and IL-15, but not IL-21 significantly enhanced the growth of CD4+CD25+ T cells (Fig. 7B; p < 0.001). The representative experiment depicted in Fig. 7C shows that IL-2 was able to accelerate the division of both CD4+CD25– and CD4+CD25+ T cells, whereas IL-21 enhanced the proliferation of CD4+CD25– T cells but not the growth of CD4+CD25+ T cells (2.5 vs 1.4% in CD3-stimulated cells). Finally, we examined the ability of IL-21, IL-2, IL-7, and IL-15 to counteract the CD4+CD25+ T cell-mediated suppression of anti-CD3-activated CD8+CD25– T cells. As indicated above, IL-21 did not overcome the CD4+CD25+ T cell-mediated block of CD8+CD25– T cell growth. By contrast, IL-2, IL-7, and IL-15 were effective in reversing the CD4+CD25+ T cell-mediated suppression of activated CD8+CD25– T cell proliferation (Fig. 7D).
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Discussion |
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The ability of IL-21 to interfere with the CD4+CD25+ T cell-mediated suppression of CD4+CD25– T cell growth was also seen when IL-21 was added 12 and 24 h later in already established cocultures of responder cells and Treg. This finding and the demonstration that Treg are efficient in inhibiting responses only up to 12 h after activation (15) suggest the possibility that IL-21 exerts directly its effects on the responding T cells and not on the Treg. This is also substantiated by the fact that the IL-21-induced block of CD4+CD25+ T cell suppression does not occur in CD8+ T cells. Our data, therefore, confirm and expand on previous studies showing that other signals, such as those provided by IL-2, IL-7, IL-15, and CD28 engagement, revert the Treg-mediated suppression of CD4+CD25– but not CD8+ T cells (20, 21). The reason why IL-21 does not protect CD8+ T cells from the suppressive action of CD4+CD25+ T cells remains unknown. It is unlikely that this simply relies on a different responsiveness of CD4+ and CD8+ T cells to IL-21, because our data clearly indicate that IL-21 enhances the proliferation of both cell types. A possibility is that IL-21 selectively induces on CD4+ T cells specific molecules that may, in turn, antagonize the activity of CD4+CD25+ T cells. A potential candidate could be the glucocorticoid-induced TNFR family-related receptor ligand, as it was recently shown that such a protein can be also expressed by T cells and provide signals that make CD4+CD25– T cells resistant to CD25+ T cell-mediated suppression (22). Studies are now in progress to address this issue.
The results presented herein also indicate that IL-21 neither enhances the percentage of Foxp3+ cells nor augments the proliferation of CD4+CD25+ T cells in cocultures with CD4+CD25– T cells. In contrast, IL-2, IL-7, and IL-15 were effective in increasing CD4+CD25+ T cell growth in accordance with previously published data (18, 19, 20, 21). In this context, it is also noteworthy that in the absence of CD4+CD25– T cells, that are known to be an important source of IL-2, almost all of the CD4+CD25+ T cells underwent apoptosis by 24 h of culture with anti-CD3+ IL-21, clearly indicating that IL-21 is not a survival factor for Treg. These data, along with the demonstration that, in other cell systems, IL-2 and IL-4, but not IL-13, are growth factors for Treg (11, 23), suggest that signaling through the common -chain that is shared by all of these cytokines is not sufficient for maintaining/prolonging CD4+CD25+ T cell survival.
In line with previously published studies, we demonstrate that IL-21 is an important growth factor for both CD4+CD25– and CD8+CD25– T cells (1), thus emphasizing the possible contribution of IL-21 to immune-mediated diseases. Indeed, we recently showed that IL-21 is produced in excess in the inflamed gut of patients with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, and that IL-21 helps sustain the ongoing Th1 cell response in the gut of patients with Crohn’s disease (3). Moreover, enhanced expression of IL-21 and IL-21R has been described in patients with systemic sclerosis (4), and up-regulation of IL-21R also occurs in synovial macrophages and fibroblasts of patients with rheumatoid arthritis (24). Studies in experimental models of autoimmune diseases have also shown that administration of IL-21 into mice enhances the recruitment of leukocytes into inflamed tissues and increases the severity of the inflammation (25). Finally, increased production of IL-21 has been described in NOD mice that are known to develop diabetes due to 
cell destruction by activated T cells (26). Overall, these findings suggest that IL-21 may activate the autoreactive T cell repertoire and trigger the effector phase of immune-mediated diseases. These effects could be also facilitated by the ability of IL-21 to counteract the suppressor function of Treg.
Since their discovery, Treg have been found to play important roles in the control of immune responses. Although they were initially described to modulate self-tolerance and to protect against autoimmunity, more recent studies have suggested that Treg may also be implicated in suppressing immune responses in infective and neoplastic diseases (7, 10). Concomitantly, several authors have shown that Treg activity can be differently modulated by inflammatory molecules, bacterial products, and tumor-derived molecules, thus raising the possibility that we can either enhance or inhibit Treg function for therapeutic purposes. In this context, our data suggest that manipulation of IL-21 activity may be a promising way to differently regulate the effect of Treg on immune cells. Therefore, in immunoinflammatory disorders in which high IL-21 associates with defective Treg function, blocking IL-21 may not only decrease bystander T cell activation, but also reconstitute the suppressor function of Treg, thus leading to the resolution of ongoing inflammatory processes. In contrast, in circumstances in which the Treg response could be detrimental rather than protective for the host, such as during viral infections and malignancies (27), administration of IL-21 could antagonize Treg, thereby contributing to relieve the virus- or tumor-induced Treg-mediated immunosuppression.
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Disclosures |
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Footnotes |
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1 This work received support from the Fondazione Umberto di Mario, Rome; the Broad Medical Research Program Foundation (Grant IBD-0154R); Ministero dell’ Istruzione, dell’ Università e della Ricerca, Grant 2004065777-004, Italy; and Giuliani SpA, Milan, Italy. 
2 Address correspondence and reprint requests to Dr. Giovanni Monteleone, Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1, Rome, Italy. E-mail address: Gi.Monteleone{at}Med.uniroma2.it
3 Abbreviations used in this paper: Treg, regulatory T cell; Ann V, annexin V.
Received for publication July 10, 2006. Accepted for publication November 7, 2006.
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production in Crohn’s disease. Gastroenterology 128: 687-694. induces a regulatory phenotype in CD4+CD25– T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172: 5149-5153. induction of transcription factor Foxp3. J. Exp. Med. 198: 1875-1886. -chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25–CD4+ precursors. J. Immunol. 175: 6107-6116. This article has been cited by other articles:
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