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* Division of Immunoregulation,
Division of Molecular Immunology, The National Institute for Medical Research, London, United Kingdom;
Department of Pathology and Microbiology, University of Bristol School of Medical Sciences, Bristol, United Kingdom; and
Dynavax Technologies, Berkeley, CA 94710
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-TReg (13), which have been isolated under particular regimens of antigenic stimulation both in vitro and in vivo. The CD4+CD25+ TReg subset represents 5–10% of the adult peripheral CD4+ T cell compartment and is involved in preventing immune pathologies, including wasting disease, autoimmune thyroiditis, gastritis, oophoritis, and orchitis (14). CD4+CD25+ TReg protect lymphopenic mice from inflammatory bowel disease (IBD), autoimmune gastritis (15), wasting disease (4), and diabetes (16), and prevent transplant rejection (17) and immune response to tumors (18, 19). IL-10 produced by CD4+CD25+ TReg is involved in protection from induced colitis (20) and allograft rejection (21), in the control of naive T cell proliferation in vivo in immunocompromised mice (22) and in the response to the pathogen Leishmania major (23). IL-10 produced by TReg derived under defined regimens of antigenic stimulation, is involved in the control of autoimmune pathologies including experimental autoimmune encephalomyelitis (EAE) (11, 12, 24). Suppression of other pathologies such as autoimmune gastritis by CD4+CD25+ TReg (3, 15, 25) is IL-10 independent (25), as is the inhibition of T cell proliferation in vitro, which is mediated by cell-cell contact (26). Most of the IL-10-producing cells described to date were heterogeneous or clones (6, 7, 8, 9, 10, 11, 12, 24, 27), and the molecular mechanisms for their derivation and full effector function are not clearly defined. For this reason, we previously devised a strategy of antigenic stimulation of naive CD4+ T cells using immunosuppressive drugs that reproducibly gave rise to a homogeneous population of IL-10-TReg (11). These IL-10-TReg could be derived from Ag-specific TCR transgenic mice on a recombination-activating gene knockout background that lack CD4+CD25+ TReg, showing that they can arise from naive CD4+ T cells not containing CD4+CD25+ TReg (11). These in vitro-derived IL-10-TReg blocked EAE, and their development and function was IL-10 dependent (11).
Recently, the forkhead/winged helix transcription factor Foxp3 was shown to be specifically expressed in CD4+CD25+ TReg and to control their development (28, 29, 30, 31). Absence or mutations in Foxp3 resulted in abrogation of their development and led to lymphoproliferative disorders, wasting disease, and IBD in mice (Refs. 29 and 30 ; reviewed in Ref.31), and lymphoproliferative disorders and autoimmune syndromes in humans (Refs.32, 33, 34, 35 ; reviewed in Refs. 31 and 36). Ectopic expression of Foxp3 in mouse CD4+CD25– T cells prevented the induction of wasting disease and IBD in lymphopenic animals by these cells, and instead rendered them suppressive both in vitro and in vivo (28, 29, 30). CD4+CD25– T cells ectopically expressing Foxp3 acquired the function to suppress induced IBD and the proliferation of CD4+CD25– T cells in vitro (28, 29, 30).
Although CD4+CD25+ TReg can produce IL-10 (20, 23), the question remains as to the relationship between these TReg and Ag-driven IL-10-TReg (7, 9, 10, 11, 12, 24, 37, 38). In this study, we addressed this issue and show for the first time that homogeneous populations of IL-10-TReg, which can arise in the absence of naturally occurring TReg (11), do not express Foxp3 and yet inhibit the proliferation of T cells with comparable efficiency to ex vivo CD4+CD25+ TReg. This study demonstrates that Foxp3 is not essential for the function of TReg to inhibit T cell proliferation. The ability to derive IL-10-TReg with Ag and immunosuppressive drugs in the absence of Foxp3 may provide useful strategies for therapeutic intervention in inflammatory diseases.
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Materials and Methods |
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BALB/c mice were used as a source of T cells and APC for in vitro studies. In some experiments, BALB/c DO11.10 mice transgenic for an OVA323–339-specific TCR
crossed back with recombination-activating gene knockout mice were used as a source of naive T cells as described (11). The Tg4 transgenic mouse expressing TCR and - chains derived from the 1934.4 T cell hybridoma specific for the N-terminal, acetylated CD4-T cell epitope of myelin basic protein (MBP) (Ac1–9) (39) was used for in vivo tolerization protocols. Mice were bred and maintained under specific pathogen-free conditions at the National Institute for Medical Research or the University of Bristol School of Medical Sciences, and used between 8 and 12 wk of age.
Isolation of T cell subsets and in vitro generation of IL-10-TReg
For the derivation of IL-10-TReg in vitro with immunosuppressive drugs (11), and the medium control population, CD4+ subsets were enriched from spleen cell suspensions and purified as naive CD4+CD62LhighCD25– T cells (>99% by MoFlo flow cytometer; Cytomation, Fort Collins, CO) (11). However, in this study, naive T cells were cultured using stimulation with immobilized anti-CD3 mAbs (10 µg/ml; clone 145.2C11; BD PharMingen, San Diego, CA) and soluble anti-CD28 mAbs (2 µg/ml; clone 37.51; BD PharMingen) in the presence of a combination of 4 x 10–8 M 1,25-dihydroxyvitamin D3 (VitD3; BIOMOL Research Labs, Plymouth Meeting, PA) and of 5 x 10–8 M dexamethasone (Dex; Sigma-Aldrich, St. Louis, MO), and in the absence of anti-cytokine mAbs (medium controls used the same protocol in the absence of the drugs). Please note that the concentration of Dex has been increased in this study from that used in the previous study (11), to ensure that IL-4 and IL-2 are not produced by IL-10-TReg, in the absence of anti-cytokine mAbs, which is a prerequisite for their regulatory function in vitro (data not shown). CD4+CD25+ TReg and CD4+CD25– control T cells were obtained from spleen cell suspensionsdepleted of B220, CD11b, and CD8-positive cells, and purified as CD4+-intermediate/CD25bright staining cells or CD4highCD25– (>96 or >99% pure, respectively) as described (14, 26). Cells were stimulated with PMA (50 ng/ml; Sigma-Aldrich) and ionomycin (500 ng/ml; Sigma-Aldrich) in the presence of brefeldin A (10 µg/ml; Sigma-Aldrich) as described (11). Cells were stained with anti-IL-2-FITC (clone JES6-5H4), anti-IL-4-PE (clone 11B11), anti-IL-10-allophycocyanin (clone JES5-16E3), and isotype controls (all BD PharMingen) to assess cytokine production at the single-cell level as described (11). Labeled cells were analyzed by FACS and the obtained data were analyzed with CellQuest software (BD Biosciences, Mountain View, CA).
In vivo tolerization protocol
The acetylated N-terminal peptide of murine MBP (Ac1–9, AcASQKRPSQR) and the high MHC-affinity analog with a tyrosine substituting the wild-type lysine in position 4 (Ac1–9[4Y]) were prepared as described (12). Priming, tolerization, and challenge protocols were performed as described (12). Briefly, Tg4 transgenic mice were either given a single intranasal (i.n.) dose of PBS or primed in vivo for 6 h by a single i.n. dose of 100 µg of Ac1–9[4Y]. Tolerance was induced by giving nine doses of Ac1–9[4Y] at regular intervals over a period of 5 wk. Six hours before sacrifice, tolerized mice were challenged with a 10th i.n. dose of Ac1–9[4Y]. Purified CD4+ T cells (>95% CD4+ as determined by FACS) were obtained by positive selection of Tg4 splenocytes as described (12). Total splenocytes from naive, primed, or tolerized Tg4 mice were activated with Ac1–9[4K] (100 µg/ml), the cognate Ag, and supernatants were collected for cytokine immunoassay after 12–60 h (12). Alternatively, cells were incubated with cognate Ag for 20 h, and brefeldin A (Sigma-Aldrich) was added for the last 6 h; then cells were permeabilized and subsequently stained for cell surface CD4 and intracellularly with anti-IL-10-PE or the isotype control-PE (all BD PharMingen). Labeled cells were analyzed by FACS.
Real-time quantitative RT-PCR
Freshly isolated T cells, primed or tolerized T cells, or in vitro-cultured T cells were stimulated for the indicated time points with immobilized anti-CD3 (2 µg/ml) and soluble anti-CD28 (2 µg/ml), or PMA (40 ng/ml) and ionomycin (100 ng/ml). RNA from the different T cell populations was extracted using RNeasy kit (Qiagen, Hilden, Germany) or by the TRIzol method for the in vivo populations, DNase treated (Roche, East Sussex, U.K.), and reverse-transcribed as described (11). cDNA was analyzed for the expression of Foxp3, IL-2, IL-10, and ubiquitin by real-time PCR assay using an ABI Prism 7000 Sequence Detection System (Applied Biosystems, Foster City, CA). Target gene mRNA expression was quantified using SYBR green (Applied Biosystems) and normalized to the ubiquitin mRNA levels.
Proliferation assays
CD4+CD25– T cells (50 x 103 cells) and the indicated numbers of IL-10-TReg or CD4+CD25+ TReg were cultured either alone or in combination (see Figs. 3 and 4). Cultures were performed in triplicate in 96-well round-bottom plates (Corning Costar, Cambridge, MA) with indicated numbers of T cell-depleted (anti-CD3; clone 17A2; BD PharMingen) and gamma-irradiated (3000 rad) spleen cells as an APC source and 0.5 µg/ml soluble anti-CD3, as described (26, 40). In some experiments, exogenous IL-2 (5 ng/ml), anti-IL10R mAb (clone 1B1.3a; 10 µg/ml; a kind gift from DNAX Research Institute (Palo Alto, CA); Ref.41), or isotype-matched control mAb were added to the cultures. In vitro proliferation was assessed by measuring incorporation of [3H]TdR (Amersham, Arlington Heights, IL) by liquid scintillation spectroscopy after pulsing with 18.5 kBq (0.5 µCi) for the last 6 h of a 72-h culture. Transwell experiments were performed in 24-well plates (Corning Costar) as described (26). Briefly, CD4+CD25– T cells (0.5 x 106 cells) were cultured with APC (0.5 x 106 cells) and anti-CD3 (0.5 µg/ml). In some cultures, TReg cells (0.25 x 106 cells) were added and separated by a semipermeable membrane (Corning Costar). Either anti-IL10R mAb (clone 1B1.3a; 10 µg/ml) or isotype-matched control mAb were added to the cultures. Alternatively, CD4+CD25– T cells (see Fig. 4Bi), IL-10-TReg, or CD4+CD25+ TReg (Bii) were labeled with CFSE (Molecular Probes, Eugene, OR) together with Thy1.2 mAbs (BD PharMingen) before the culture and analyzed for progressive halving of the CFSE label by FACS after 72 h.
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Results |
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To investigate the possible relationship between CD4+CD25+ TReg and Ag-driven IL-10-TReg, we analyzed the expression of Foxp3 in both populations. Homogeneous populations of IL-10-TReg were obtained in vitro by stimulating naive CD4+ T cells in the presence of a combination of the anti-inflammatory drugs VitD3 and Dex, as we have previously described (11). These cultures resulted consistently in >75% IL-10-producing T cells, upon restimulation for 4 h, which produced no detectable IL-2, IL-4 (Fig. 1A), or IFN-
(data not shown; Ref.11), whereas cells cultured in the absence of the drugs contained low numbers of IL-10-, IL-4-, IL-2- (Fig. 1A), and IFN--producing cells (data not shown; Ref.11). In contrast, freshly isolated CD4+CD25– T cells or CD4+CD25+ TReg stimulated for 4 h in vitro produced very little IL-2 or IL-10 protein (data not shown).
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In vivo Ag-driven IL-10-TReg do not express Foxp3
To address whether other regimens for inducing IL-10-TReg such as peptide Ag stimulation in vivo (12) resulted in increased Foxp3 expression, we used a regimen of repetitive i.n. administration of the peptide Ac1–9[4Y] of MBP in the Tg4 transgenic mouse model to obtain in vivo Ag-driven IL-10-TReg as we have previously described (12, 24). Ex vivo-stimulated total CD4+ Tg4 T cells from i.n. tolerized mice contained 
10% of IL-10-producing cells (Fig. 2A). In contrast, total CD4+ Tg4 T cells from nontolerized mice contained <1% of IL-10-producing cells (data not shown). Differential production of either IL-10 or IL-2 by CD4+ Tg4 T cells from naive, primed, and i.n. tolerized mice was investigated in more depth in a kinetic immunoassay (Fig. 2B). CD4+ T cells from PBS-treated or primed mice produced high IL-2 levels upon restimulation in vitro with the cognate Ag and APC with a peak between 48 and 72 h, decreased by 96 h, reflecting IL-2 consumption/regulation. CD4+ T cells from tolerized mice produced little to no IL-2 (Fig. 2B). IL-10 production was maximal in CD4+ T cells from tolerized mice upon restimulation in vitro and maintained until 96 h, but low to undetectable in CD4+ T cells from primed or naive mice, respectively.
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IL-10-TReg inhibit T cell proliferation in vitro independently of IL-10
In vivo-derived IL-10-TReg inhibit naive T cell proliferation in vitro in an IL-10-independent fashion (10, 12); however, these populations were heterogeneous and may have contained naturally occurring TReg. We addressed this issue using homogeneous IL-10-TReg derived in vitro with immunosuppressive drugs, which produce large amounts of IL-10, do not express Foxp3, and arise independently of naturally occurring TReg (Fig. 1; Ref.11). IL-10-TReg inhibited the proliferation of CD4+CD25– T cells in response to anti-CD3 mAb, in the context of irradiated T-depleted spleen APC, at a ratio of one regulator to two responders, similarly to that previously reported for CD4+CD25+ TReg (Fig. 3A). CD4+ T cells generated in vitro in the absence of the drugs produced IL-2 (Fig. 1A) and failed to inhibit CD4+CD25– T cell proliferation (data not shown). Whereas CD4+CD25+ TReg failed to proliferate when cultured with APC and anti-CD3 in the absence of CD4+CD25– T cells (5, 26, 40) (Fig. 3A), IL-10-TReg displayed a low basal proliferation level (Fig. 3A). This seemingly raised the background proliferation levels of proliferation in the mixed cultures masking the full extent of their inhibition of CD4+CD25– T cell proliferation.
Blocking IL-10R-mediated signaling during coculture of homogeneous populations of IL-10-TReg with CD4+CD25– T cells at a ratio of 1:8 (and other ratios; data not shown) did not affect their inhibition of T cell proliferation in vitro (Fig. 3B), similarly to cultures using CD4+CD25+ TReg whose function in vitro is IL-10 independent (B; Refs. 3 and 26). Neither anti-TGF- (together with anti-IL-10R mAbs or alone) nor anti-CTLA-4 mAbs showed any effect on T cell suppression by either IL-10-TReg (data not shown) or by CD4+CD25+ TReg as previously shown in vitro (26), despite the enhanced levels of CTLA-4 by the IL-10-TReg (data not shown; Ref.12). Moreover, because IL-10-TReg expressed enhanced levels of glucocorticoid-induced TNFR family-related gene (GITR) (data not shown) and comparable to those of activated CD4+CD25+ TReg (42, 43), we tested whether GITR cross-linking would play a role in this in vitro assay. Anti-GITR mAbs overcame the suppression, but in this case, the enhancement of activated CD4+CD25– T cell proliferation accounted for this effect (data not shown). Exogenous IL-2 completely abolished the inhibition of CD4+CD25– T cell proliferation by either IL-10-TReg (Fig. 3B) or CD4+CD25+ TReg (Fig. 3B; Ref.26) and significantly raised the basal proliferation level of the CD4+CD25– T cells and both TReg populations (B).
To address the issue whether cell-cell contact would mediate the suppression of naive T cell proliferation by IL-10-TReg, Transwell culture chambers were used. Separation of naive T cells from either TReg population resulted in the abrogation of suppression of T cell proliferation (Fig. 3C) in response to anti-CD3 mAb, in the context of irradiated T-depleted spleen APC, as opposed to cultures in which both naive T cells and TReg were present in the lower chamber of the culture. Furthermore, blocking IL-10R-mediated signaling did not affect this abrogation of suppression.
Threshold of activation determines T regulatory effectiveness in vitro
We subsequently addressed whether the inhibitory potential of these IL-10-TReg is comparable to that of CD4+CD25+ TReg. IL-10-TReg and CD4+CD25+ TReg were titrated in vitro to compare their efficiency to inhibit CD4+CD25– T cell proliferation in response to APC and anti-CD3 mAb. Strikingly, IL-10-TReg were as efficient as CD4+CD25+ TReg in suppressing CD4+CD25– T cell proliferation at regulator-to-responder ratios ranging from 1:1 to 1:8 (Fig. 4A, upper panels, •). However, the level of CD4+CD25– T cell proliferation was reduced to <500 cpm with CD4+CD25+ TReg (background levels) and to only 1000 cpm with IL-10-TReg (Fig. 4A, upper panels, •). This can be accounted for by the basal proliferation level of IL-10-TReg alone in contrast to the totally unresponsive CD4+CD25+ TReg (Fig. 4A, top panel, 
). Both TReg lost suppressive activity at TReg-to-T cell ratios of <1:4 when the activation threshold was altered by raising the amount of APC 5-fold in the system (Fig. 4A, lower panels), although IL-10-TReg were much less efficient than CD4+CD25+ TReg (A, lower panels, •). Again, this reflected the basal proliferation of IL-10-TReg themselves vs CD4+CD25+ TReg (Fig. 4A, lower panels, ). IL-10-TReg also seemed to control their own proliferation at high cell numbers (Fig. 4A, left lower panel, ).
To clarify the ability of IL-10-TReg to inhibit T cell proliferation independently of their own proliferation, and to obtain an accurate assessment of their efficiency as compared with CD4+CD25+ TReg, we used CFSE-labeled cells. CFSE experiments demonstrated that, despite their basal proliferation level in response to APC and anti-CD3, IL-10-TReg were as potent as CD4+CD25+ TReg in controlling the proliferation of CD4+CD25– T cells at a ratio of 1:2 TReg to CD4+CD25– T cells (Fig. 4Bi, left-hand panels) at low activation thresholds (50 x 103 APC, which are the numbers used in the original studies for CD4+CD25+ TReg (26)). By raising 5-fold the amount of APC in the cultures, CD4+CD25+ TReg retained their inhibitory potential, whereas IL-10-TReg became slightly less efficient (Fig. 4Bi, right-hand panel). Thus, the efficiency of IL-10-TReg vs CD4+CD25+ TReg was similar, although this was masked in cocultures analyzed by [3H]TdR incorporation by the different basal proliferation levels by each TReg population. In keeping with the [3H]TdR incorporation data (Fig. 3B and data not shown), IL-10-TReg exerted their inhibitory function in vitro via an IL-10-independent mechanism as observed by CFSE decay (Fig. 4Bi). In a number of experiments with very high APC numbers (250 x 103) and varying IL-10-TReg-to-T cell ratios, a minor but nonreproducible effect of anti-IL-10R mAbs was occasionally observed, which in part was explained by a minor enhancement of proliferation of the IL-10-TReg themselves. However, in total, CFSE experiments also showed that IL-10-TReg themselves proliferate to a low level, in contrast to naturally occurring CD4+CD25+ TReg, which never proliferate (Fig. 4Bii), and that blocking IL-10R signaling did not significantly alter their basal level of proliferation.
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Discussion |
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Mutations or absence of Foxp3 in mice and humans results in a lymphoproliferative disease characterized by cachexia and multiorgan lymphocytic infiltrates (Refs.29, 30, 31, 32, 33, 34, 35 ; reviewed in Refs. 31 and 36). Foxp3-expressing CD4+CD25+ TReg inhibited the development of this disease when administered to neonatal Scurfy mutant mice (30). Furthermore, ectopic expression of Foxp3 in CD4+CD25– T cells prevented induction of lymphoproliferative and wasting diseases, and IBD by these cells in lymphopenic hosts, and rendered them suppressive both in vitro and in vivo (28, 29, 30). We show that Foxp3 expression is not necessary for TReg function to inhibit T cell proliferation in vitro, but may engender cells with this capacity via the induction of as-yet-unknown genes. IL-10-TReg that develop from naive T cells in the absence of CD4+CD25+ TReg (11), inhibited T cell proliferation in vitro with a similar efficiency to that of CD4+CD25+ TReg and may acquire this property postnatally upon certain conditions of Ag encounter by CD4+ T cells in the periphery.
Despite the differences in Foxp3 expression in CD4+CD25+ TReg and IL-10-TReg, both populations inhibited T cell proliferation in vitro, and expressed little to no IL-2 (Fig. 1B), which may be a requisite for their regulatory function. Foxp3 was suggested to act as a negative modulator of IL-2 transcription (32). This can be clearly achieved in IL-10-TReg by different mechanisms including antigenic stimulation in the presence of immunosuppressive drugs, or by peptide-antigenic regimens leading to anergy (10, 11, 12, 27, 45). Both CD4+CD25+ and IL-10-TReg express enhanced levels of the IL-2R -chain CD25 (data not shown), a requirement for their suppressive function if IL-2 consumption is a component of this in vitro suppression as suggested (T. Barthlott and B. Stockinger, unpublished observations). To date, the mechanism(s) whereby inhibition of proliferation and expression of IL-2 mRNA in T cells by CD4+CD25+ TReg (3, 26) and IL-10-TReg is achieved is unclear.
We show that homogeneous populations of IL-10-TReg, despite production of large amounts of IL-10, inhibit T cell proliferation in vitro in an IL-10-independent and cell contact-dependent fashion. In vitro assays were performed identically to assays described for CD4+CD25+ TReg (3, 26, 40) and included different ratios of TReg to CD4+ T cells, and tested different numbers of APC. Other TReg, including in vivo Ag-driven IL-10-secreting TReg (10, 12), which produce low levels of IL-10 and are heterogeneous, also inhibit T cell proliferation in vitro apparently via an IL-10-independent mechanism. However, one study suggested that IL-10 may partially mediate the inhibitory effect of the so-called Tr1 IL-10-TReg, although it is of note that neutralization of IL-10 never completely reversed the suppressive effect on T cell proliferation (7). These different results may reflect heterogeneity of TReg at various levels, including IL-10 production or the number of regulators vs T cells used in the assays. We now rule out these possibilities, confirming that even IL-10-TReg producing high IL-10 levels significantly inhibit T cell proliferation in the absence of IL-10 activity. The source of "naive" CD4+ T cells and possible contamination with effectors, the APC type and number used and their activation status may explain such discrepancies (7). We occasionally observed a minimal but nonreproducible effect of anti-IL-10R mAbs in relieving suppression of T cells by IL-10 TReg, at high APC number, and at certain T cell vs TReg ratios (data not shown), and possibly due to a minimal enhancement of proliferation of IL-10-TReg themselves in the presence of anti-IL-10R mAbs. Our study now shows definitively with the use of CFSE-labeled cells that the major suppression by IL-10-TReg of T cell proliferation in vitro under the conditions described by Thornton and Shevach (26) for CD4+CD25+ TReg is independent of IL-10.
In contrast to the lack of a role for IL-10 in the in vitro suppression of T cell proliferation by IL-10-TReg or CD4+CD25+ TReg, IL-10 is involved in the inhibition of IBD (20, 46) and wasting disease (20, 22), in the control of in vivo expansion of naive CD4+ T cells in lymphopenic hosts (22), and in the inhibition of EAE (11). These effects may be achieved via the inhibition of APC function by IL-10 (44, 46). In vitro assays used for inhibition of naive T cell proliferation by TReg may not reveal a role for IL-10 as a result of the duration of the assay and the APC type, and may not reflect the extent of APC activation that may occur in vivo. Toll-like receptor ligation of bone marrow-derived dendritic cells overcomes inhibition of naive T cell proliferation by CD4+CD25+ TReg partially through IL-6 production (47). Because IL-10’s major effects are to inhibit APC function, including production of proinflammatory cytokines (44, 48, 49), it is likely that IL-10 plays a role in TReg function upon activation of the innate immune response (44, 46, 50, 51). The in vitro assay showing robust inhibition of naive T cell proliferation by CD4+CD25+ TReg and IL-10-TReg independently of IL-10 may thus reflect the first layer of regulation in vivo before activation of the innate immune response. These findings are not incompatible with the hypothesis that control of cell numbers in vivo in lymphopenic mice and possibly intact mice, may first be subject to other mechanisms of regulation before a participation of IL-10 is evoked in suppression (3, 5, 36, 52).
IL-10-secreting cells can be induced by both in vitro and in vivo regimens of antigenic stimulation (6, 7, 8, 9, 10, 11, 12, 24, 27). However, the mechanisms underlying the induction of IL-10 expression in TReg and the possible relationship between IL-10 and Foxp3 expression is unclear (28, 29, 30, 31, 36). Studies addressing this issue in CD4+CD25– T cells ectopically expressing Foxp3 vs CD4+CD25+ TReg yielded conflicting results (28, 29, 30). We now resolve this issue by showing that homogeneous populations of IL-10-TReg do not express Foxp3. It is of note that enhanced IL-10 expression in IL-10-TReg is always mirrored by a significant decrease in IL-2 expression (Figs. 1 and 2; Refs. 11 and 12) and that IL-2 expression is also absent in Foxp3-expressing CD4+CD25+ TReg, suggesting that IL-2 is extinguished by different mechanisms in both TReg types.
Finally, we demonstrate in this study that IL-10-TReg, which we have previously shown to have regulatory capacity in vivo (11, 12), do not express Foxp3 and yet inhibit naive T cell proliferation in vitro similarly to CD4+CD25+ TReg. These observations and the fact that we can derive these IL-10-TReg with immunosuppressive drugs from naive CD4+ T cells by antigenic stimulation in the absence of other naturally occurring TReg (11), and in the absence of Foxp3, suggests their potential use in early development in immunotherapy of inflammatory diseases. Withdrawal of immunosuppressive drugs later in development would ensure that the host could respond appropriately to environmental pathogens but be tolerant to self Ags encountered by T cells upon exit from the thymus.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Drs. Anne O’Garra or Pedro L. Vieira, Division of Immunoregulation, National Institute for Medical Research, London NW7 1AA, United Kingdom. E-mail addresses: aogarra{at}nimr.mrc.ac.uk or pvieira{at}nimr.mrc.ac.uk
3 Abbreviations used in this paper: TReg, regulatory T cell; IBD, inflammatory bowel disease; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; VitD3, 1,25-dihydroxyvitamin D3; Dex, dexamethasone; i.n., intranasal; GITR, glucocorticoid-induced TNFR family-related gene.
Received for publication December 22, 2003. Accepted for publication March 1, 2004.
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References |
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but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlowCD4+ T cells. J. Exp. Med. 183:2669.-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
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B. Haringer, L. Lozza, B. Steckel, and J. Geginat Identification and characterization of IL-10/IFN-{gamma}-producing effector-like T cells with regulatory function in human blood J. Exp. Med., May 11, 2009; 206(5): 1009 - 1017. [Abstract] [Full Text] [PDF]
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C. L. Maynard, R. D. Hatton, W. S. Helms, J. R. Oliver, C. B. Stephensen, and C. T. Weaver Contrasting roles for all-trans retinoic acid in TGF-{beta}-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells J. Exp. Med., February 16, 2009; 206(2): 343 - 357. [Abstract] [Full Text] [PDF]
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J.-B. Sun, C.-F. Flach, C. Czerkinsky, and J. Holmgren B Lymphocytes Promote Expansion of Regulatory T Cells in Oral Tolerance: Powerful Induction by Antigen Coupled to Cholera Toxin B Subunit J. Immunol., December 15, 2008; 181(12): 8278 - 8287. [Abstract] [Full Text] [PDF]
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N. B. Marshall, W. R. Vorachek, L. B. Steppan, D. V. Mourich, and N. I. Kerkvliet Functional Characterization and Gene Expression Analysis of CD4+CD25+ Regulatory T Cells Generated in Mice Treated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin J. Immunol., August 15, 2008; 181(4): 2382 - 2391. [Abstract] [Full Text] [PDF]
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M. Kasprzycka, Q. Zhang, A. Witkiewicz, M. Marzec, M. Potoczek, X. Liu, H. Y. Wang, M. Milone, S. Basu, J. Mauger, et al. {gamma}c-Signaling Cytokines Induce a Regulatory T Cell Phenotype in Malignant CD4+ T Lymphocytes J. Immunol., August 15, 2008; 181(4): 2506 - 2512. [Abstract] [Full Text] [PDF]
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S. K. Alford, G. D. Longmore, W. F. Stenson, and C. Kemper CD46-Induced Immunomodulatory CD4+ T Cells Express the Adhesion Molecule and Chemokine Receptor Pattern of Intestinal T Cells J. Immunol., August 15, 2008; 181(4): 2544 - 2555. [Abstract] [Full Text] [PDF]
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A. Wakkach, S. Augier, J.-P. Breittmayer, C. Blin-Wakkach, and G. F. Carle Characterization of IL-10-Secreting T Cells Derived from Regulatory CD4+CD25+ Cells by the TIRC7 Surface Marker J. Immunol., May 1, 2008; 180(9): 6054 - 6063. [Abstract] [Full Text] [PDF]
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T. Tilburgs, D. L. Roelen, B. J. van der Mast, G. M. de Groot-Swings, C. Kleijburg, S. A. Scherjon, and F. H. Claas Evidence for a Selective Migration of Fetus-Specific CD4+CD25bright Regulatory T Cells from the Peripheral Blood to the Decidua in Human Pregnancy J. Immunol., April 15, 2008; 180(8): 5737 - 5745. [Abstract] [Full Text] [PDF]
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A. J. Currie, R. G. van der Most, S. A. Broomfield, A. C. Prosser, M. G. Tovey, and B. W. S. Robinson Targeting the Effector Site with IFN-{alpha}{beta}-Inducing TLR Ligands Reactivates Tumor-Resident CD8 T Cell Responses to Eradicate Established Solid Tumors J. Immunol., February 1, 2008; 180(3): 1535 - 1544. [Abstract] [Full Text] [PDF]
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G. Deniz, G. Erten, U. C. Kucuksezer, D. Kocacik, C. Karagiannidis, E. Aktas, C. A. Akdis, and M. Akdis Regulatory NK Cells Suppress Antigen-Specific T Cell Responses J. Immunol., January 15, 2008; 180(2): 850 - 857. [Abstract] [Full Text] [PDF]
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W. Hansen, A. M. Westendorf, S. Reinwald, D. Bruder, S. Deppenmeier, L. Groebe, M. Probst-Kepper, A. D. Gruber, R. Geffers, and J. Buer Chronic Antigen Stimulation In Vivo Induces a Distinct Population of Antigen-Specific Foxp3 CD25 Regulatory T Cells J. Immunol., December 15, 2007; 179(12): 8059 - 8068. [Abstract] [Full Text] [PDF]
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A. Giorgini and A. Noble Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts J. Leukoc. Biol., November 1, 2007; 82(5): 1053 - 1061. [Abstract] [Full Text] [PDF]
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W. Niedbala, B. Cai, H. Liu, N. Pitman, L. Chang, and F. Y. Liew Nitric oxide induces CD4+CD25+ Foxp3 regulatory T cells from CD4+CD25 T cells via p53, IL-2, and OX40 PNAS, September 25, 2007; 104(39): 15478 - 15483. [Abstract] [Full Text] [PDF]
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E. J. Beswick, I. V. Pinchuk, S. Das, D. W. Powell, and V. E. Reyes Expression of the Programmed Death Ligand 1, B7-H1, on Gastric Epithelial Cells after Helicobacter pylori Exposure Promotes Development of CD4+ CD25+ FoxP3+ Regulatory T Cells Infect. Immun., September 1, 2007; 75(9): 4334 - 4341. [Abstract] [Full Text] [PDF]
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P. Reichardt, B. Dornbach, S. Rong, S. Beissert, F. Gueler, K. Loser, and M. Gunzer Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse Blood, September 1, 2007; 110(5): 1519 - 1529. [Abstract] [Full Text] [PDF]
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M. Pyzik and C. A. Piccirillo TGF-{beta}1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets J. Leukoc. Biol., August 1, 2007; 82(2): 335 - 346. [Abstract] [Full Text] [PDF]
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J. M. M. den Haan, G. Kraal, and M. J. Bevan Cutting Edge: Lipopolysaccharide Induces IL-10-Producing Regulatory CD4+ T Cells That Suppress the CD8+ T Cell Response J. Immunol., May 1, 2007; 178(9): 5429 - 5433. [Abstract] [Full Text] [PDF]
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V. Preller, A. Gerber, S. Wrenger, M. Togni, D. Marguet, J. Tadje, U. Lendeckel, C. Rocken, J. Faust, K. Neubert, et al. TGF-beta1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26 J. Immunol., April 1, 2007; 178(7): 4632 - 4640. [Abstract] [Full Text] [PDF]
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J. Stein-Streilein and A. W. Taylor An eye's view of T regulatory cells J. Leukoc. Biol., March 1, 2007; 81(3): 593 - 598. [Abstract] [Full Text] [PDF]
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D. Jankovic, M. C. Kullberg, C. G. Feng, R. S. Goldszmid, C. M. Collazo, M. Wilson, T. A. Wynn, M. Kamanaka, R. A. Flavell, and A. Sher Conventional T-bet+Foxp3- Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection J. Exp. Med., February 19, 2007; 204(2): 273 - 283. [Abstract] [Full Text] [PDF]
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A. Joetham, K. Takada, C. Taube, N. Miyahara, S. Matsubara, T. Koya, Y.-H. Rha, A. Dakhama, and E. W. Gelfand Naturally Occurring Lung CD4+CD25+ T Cell Regulation of Airway Allergic Responses Depends on IL-10 Induction of TGF-beta J. Immunol., February 1, 2007; 178(3): 1433 - 1442. [Abstract] [Full Text] [PDF]
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J. Ochoa-Reparaz, C. Riccardi, A. Rynda, S. Jun, G. Callis, and D. W. Pascual Regulatory T Cell Vaccination without Autoantigen Protects against Experimental Autoimmune Encephalomyelitis J. Immunol., February 1, 2007; 178(3): 1791 - 1799. [Abstract] [Full Text] [PDF]
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H. H. Uhlig, J. Coombes, C. Mottet, A. Izcue, C. Thompson, A. Fanger, A. Tannapfel, J. D. Fontenot, F. Ramsdell, and F. Powrie Characterization of Foxp3+CD4+CD25+ and IL-10-Secreting CD4+CD25+ T Cells during Cure of Colitis J. Immunol., November 1, 2006; 177(9): 5852 - 5860. [Abstract] [Full Text] [PDF]
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P. Grimbert, S. Bouguermouh, N. Baba, T. Nakajima, Z. Allakhverdi, D. Braun, H. Saito, M. Rubio, G. Delespesse, and M. Sarfati Thrombospondin/CD47 Interaction: A Pathway to Generate Regulatory T Cells from Human CD4+CD25- T Cells in Response to Inflammation J. Immunol., September 15, 2006; 177(6): 3534 - 3541. [Abstract] [Full Text] [PDF]
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Q. Ding, L. Lu, B. Wang, Y. Zhou, Y. Jiang, X. Zhou, L. Xin, Z. Jiao, and K.-Y. Chou B7H1-Ig Fusion Protein Activates the CD4+ IFN-{gamma} Receptor+ Type 1 T Regulatory Subset through IFN-{gamma}-Secreting Th1 Cells J. Immunol., September 15, 2006; 177(6): 3606 - 3614. [Abstract] [Full Text] [PDF]
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T. Ito, Y.-H. Wang, O. Duramad, S. Hanabuchi, O. A. Perng, M. Gilliet, F. X.-F. Qin, and Y.-J. Liu OX40 ligand shuts down IL-10-producing regulatory T cells PNAS, August 29, 2006; 103(35): 13138 - 13143. [Abstract] [Full Text] [PDF]
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M. Mahic, S. Yaqub, C. C. Johansson, K. Tasken, and E. M. Aandahl FOXP3+CD4+CD25+ Adaptive Regulatory T Cells Express Cyclooxygenase-2 and Suppress Effector T Cells by a Prostaglandin E2-Dependent Mechanism J. Immunol., July 1, 2006; 177(1): 246 - 254. [Abstract] [Full Text] [PDF]
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K. Wing, Z. Fehervari, and S. Sakaguchi Emerging possibilities in the development and function of regulatory T cells Int. Immunol., July 1, 2006; 18(7): 991 - 1000. [Abstract] [Full Text] [PDF]
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S. Rutella, G. Bonanno, A. Procoli, A. Mariotti, D. G. de Ritis, A. Curti, S. Danese, G. Pessina, S. Pandolfi, F. Natoni, et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features Blood, July 1, 2006; 108(1): 218 - 227. [Abstract] [Full Text] [PDF]
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M. Kasprzycka, M. Marzec, X. Liu, Q. Zhang, and M. A. Wasik From the Cover: Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3 PNAS, June 27, 2006; 103(26): 9964 - 9969. [Abstract] [Full Text] [PDF]
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A. Sumoza-Toledo, A. D. Eaton, and A. Sarukhan Regulatory T Cells Inhibit Protein Kinase C{theta} Recruitment to the Immune Synapse of Naive T Cells with the Same Antigen Specificity J. Immunol., May 15, 2006; 176(10): 5779 - 5787. [Abstract] [Full Text] [PDF]
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K. S. Nicolson, E. J. O'Neill, A. Sundstedt, H. B. Streeter, S. Minaee, and D. C. Wraith Antigen-Induced IL-10+ Regulatory T Cells Are Independent of CD25+ Regulatory Cells for Their Growth, Differentiation, and Function J. Immunol., May 1, 2006; 176(9): 5329 - 5337. [Abstract] [Full Text] [PDF]
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M. S. Longhi, M. J. Hussain, R. R. Mitry, S. K. Arora, G. Mieli-Vergani, D. Vergani, and Y. Ma Functional Study of CD4+CD25+ Regulatory T Cells in Health and Autoimmune Hepatitis J. Immunol., April 1, 2006; 176(7): 4484 - 4491. [Abstract] [Full Text] [PDF]
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C. Chen, W.-h. Lee, L. Zhong, and C.-P. Liu Regulatory T Cells Can Mediate Their Function through the Stimulation of APCs to Produce Immunosuppressive Nitric Oxide J. Immunol., March 15, 2006; 176(6): 3449 - 3460. [Abstract] [Full Text] [PDF]
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J. Shoemaker, M. Saraiva, and A. O'Garra GATA-3 Directly Remodels the IL-10 Locus Independently of IL-4 in CD4+ T Cells J. Immunol., March 15, 2006; 176(6): 3470 - 3479. [Abstract] [Full Text] [PDF]
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C. Veldman, A. Pahl, S. Beissert, W. Hansen, J. Buer, D. Dieckmann, G. Schuler, and M. Hertl Inhibition of the transcription factor foxp3 converts desmoglein 3-specific type 1 regulatory T cells into th2-like cells. J. Immunol., March 1, 2006; 176(5): 3215 - 3222. [Abstract] [Full Text] [PDF]
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S. R. Mayack and L. J. Berg Cutting Edge: An Alternative Pathway of CD4+ T Cell Differentiation Is Induced Following Activation in the Absence of {gamma}-Chain-Dependent Cytokine Signals J. Immunol., February 15, 2006; 176(4): 2059 - 2063. [Abstract] [Full Text] [PDF]
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W. Barchet, J. D. Price, M. Cella, M. Colonna, S. K. MacMillan, J. P. Cobb, P. A. Thompson, K. M. Murphy, J. P. Atkinson, and C. Kemper Complement-induced regulatory T cells suppress T-cell responses but allow for dendritic-cell maturation Blood, February 15, 2006; 107(4): 1497 - 1504. [Abstract] [Full Text] [PDF]
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C. K. Asiedu, K. J. Goodwin, G. Balgansuren, S. M. Jenkins, S. Le Bas-Bernardet, U. Jargal, D. M. Neville Jr, and J. M. Thomas Elevated T Regulatory Cells in Long-Term Stable Transplant Tolerance in Rhesus Macaques Induced by Anti-CD3 Immunotoxin and Deoxyspergualin J. Immunol., December 15, 2005; 175(12): 8060 - 8068. [Abstract] [Full Text] [PDF]
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P. Stock, O. Akbari, R. H. DeKruyff, and D. T. Umetsu Respiratory Tolerance Is Inhibited by the Administration of Corticosteroids J. Immunol., December 1, 2005; 175(11): 7380 - 7387. [Abstract] [Full Text] [PDF]
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M. S. Wilson, M. D. Taylor, A. Balic, C. A.M. Finney, J. R. Lamb, and R. M. Maizels Suppression of allergic airway inflammation by helminth-induced regulatory T cells J. Exp. Med., November 7, 2005; 202(9): 1199 - 1212. [Abstract] [Full Text] [PDF]
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S. Mocellin, F. M. Marincola, and H. A. Young Interleukin-10 and the immune response against cancer: a counterpoint J. Leukoc. Biol., November 1, 2005; 78(5): 1043 - 1051. [Abstract] [Full Text] [PDF]
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C. J. Funatake, N. B. Marshall, L. B. Steppan, D. V. Mourich, and N. I. Kerkvliet Cutting Edge: Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-p-dioxin Generates a Population of CD4+CD25+ Cells with Characteristics of Regulatory T Cells J. Immunol., October 1, 2005; 175(7): 4184 - 4188. [Abstract] [Full Text] [PDF]
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A. K. Kriegeskorte, F. E. Gebhardt, S. Porcellini, M. Schiemann, C. Stemberger, T. J. Franz, K. M. Huster, L. N. Carayannopoulos, W. M. Yokoyama, M. Colonna, et al. NKG2D-independent suppression of T cell proliferation by H60 and MICA PNAS, August 16, 2005; 102(33): 11805 - 11810. [Abstract] [Full Text] [PDF]
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C. B. Stober, U. G. Lange, M. T. M. Roberts, A. Alcami, and J. M. Blackwell IL-10 from Regulatory T Cells Determines Vaccine Efficacy in Murine Leishmania major Infection J. Immunol., August 15, 2005; 175(4): 2517 - 2524. [Abstract] [Full Text] [PDF]
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B. V. Aruna, M. Sela, and E. Mozes Suppression of myasthenogenic responses of a T cell line by a dual altered peptide ligand by induction of CD4+CD25+ regulatory cells PNAS, July 19, 2005; 102(29): 10285 - 10290. [Abstract] [Full Text] [PDF]
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J. D. Price, J. Schaumburg, C. Sandin, J. P. Atkinson, G. Lindahl, and C. Kemper Induction of a Regulatory Phenotype in Human CD4+ T Cells by Streptococcal M Protein J. Immunol., July 15, 2005; 175(2): 677 - 684. [Abstract] [Full Text] [PDF]
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M. Saraiva{paragraph}, J. R. Christensen, A. V. Tsytsykova, A. E. Goldfeld, S. C. Ley, D. Kioussis, and A. O'Garra Identification of a Macrophage-Specific Chromatin Signature in the IL-10 Locus J. Immunol., July 15, 2005; 175(2): 1041 - 1046. [Abstract] [Full Text] [PDF]
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P. Yu, R. K. Gregg, J. J. Bell, J. S. Ellis, R. Divekar, H.-H. Lee, R. Jain, H. Waldner, J. C. Hardaway, M. Collins, et al. Specific T Regulatory Cells Display Broad Suppressive Functions against Experimental Allergic Encephalomyelitis upon Activation with Cognate Antigen J. Immunol., June 1, 2005; 174(11): 6772 - 6780. [Abstract] [Full Text] [PDF]
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M. D. Taylor, L. LeGoff, A. Harris, E. Malone, J. E. Allen, and R. M. Maizels Removal of Regulatory T Cell Activity Reverses Hyporesponsiveness and Leads to Filarial Parasite Clearance In Vivo J. Immunol., April 15, 2005; 174(8): 4924 - 4933. [Abstract] [Full Text] [PDF]
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D. W. Smith and C. Nagler-Anderson Preventing Intolerance: The Induction of Nonresponsiveness to Dietary and Microbial Antigens in the Intestinal Mucosa J. Immunol., April 1, 2005; 174(7): 3851 - 3857. [Abstract] [Full Text] [PDF]
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T. Bonnefoix, P. Bonnefoix, P. Perron, J.-Q. Mi, W. F. Ng, R. Lechler, J.-C. Bensa, J.-Y. Cahn, and D. Leroux Quantitating Effector and Regulatory T Lymphocytes in Immune Responses by Limiting Dilution Analysis Modeling J. Immunol., March 15, 2005; 174(6): 3421 - 3431. [Abstract] [Full Text] [PDF]
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Y. Cong, A. Konrad, N. Iqbal, R. D. Hatton, C. T. Weaver, and C. O. Elson Generation of Antigen-Specific, Foxp3-Expressing CD4+ Regulatory T Cells by Inhibition of APC Proteosome Function J. Immunol., March 1, 2005; 174(5): 2787 - 2795. [Abstract] [Full Text] [PDF]
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J. Liu, T. Miwa, B. Hilliard, Y. Chen, J. D. Lambris, A. D. Wells, and W.-C. Song The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo J. Exp. Med., February 22, 2005; 201(4): 567 - 577. [Abstract] [Full Text] [PDF]
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M. K. Levings, S. Gregori, E. Tresoldi, S. Cazzaniga, C. Bonini, and M. G. Roncarolo Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells Blood, February 1, 2005; 105(3): 1162 - 1169. [Abstract] [Full Text] [PDF]
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P. O. Anderson, A. Sundstedt, Z. Yazici, S. Minaee, R. Woolf, K. Nicolson, N. Whitley, L. Li, S. Li, D. C. Wraith, et al. IL-2 Overcomes the Unresponsiveness but Fails to Reverse the Regulatory Function of Antigen-Induced T Regulatory Cells J. Immunol., January 1, 2005; 174(1): 310 - 319. [Abstract] [Full Text] [PDF]
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M. A. Curotto de Lafaille, A. C. Lino, N. Kutchukhidze, and J. J. Lafaille CD25- T Cells Generate CD25+Foxp3+ Regulatory T Cells by Peripheral Expansion J. Immunol., December 15, 2004; 173(12): 7259 - 7268. [Abstract] [Full Text] [PDF]
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H. Yagi, T. Nomura, K. Nakamura, S. Yamazaki, T. Kitawaki, S. Hori, M. Maeda, M. Onodera, T. Uchiyama, S. Fujii, et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells Int. Immunol., November 1, 2004; 16(11): 1643 - 1656. [Abstract] [Full Text] [PDF]
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H.-B. Park, D.-J. Paik, E. Jang, S. Hong, and J. Youn Acquisition of anergic and suppressive activities in transforming growth factor-{beta}-costimulated CD4+CD25- T cells Int. Immunol., August 1, 2004; 16(8): 1203 - 1213. [Abstract] [Full Text] [PDF]
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A. S. McKee and E. J. Pearce CD25+CD4+ Cells Contribute to Th2 Polarization during Helminth Infection by Suppressing Th1 Response Development J. Immunol., July 15, 2004; 173(2): 1224 - 1231. [Abstract] [Full Text] [PDF]
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