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Cutting Edge: Autocrine TGF-β Sustains Default Tolerogenesis by IDO-Competent Dendritic Cells¹

Maria L. Belladonna^2,*, Claudia Volpi^*, Roberta Bianchi^*, Carmine Vacca^*, Ciriana Orabona^*, Maria T. Pallotta^*, Louis Boon, Stefania Gizzi, Maria C. Fioretti^*, Ursula Grohmann^* and Paolo Puccetti^2,*

^* Department of Experimental Medicine and Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; and Bioceros B.V., Utrecht, The Netherlands

	Abstract

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CD8^– and CD8⁺ dendritic cells (DCs) are distinct subsets of mouse splenic accessory cells with opposite but flexible programs of Ag presentation, leading to immunogenic and tolerogenic responses, respectively. In this study, we show that the default tolerogenic function of CD8⁺ DCs relies on autocrine TGF-β, which sustains the activation of IDO in response to environmental stimuli. CD8^– DCs do not produce TGF-β, yet externally added TGF-β induces IDO and turns those cells from immunogenic into tolerogenic cells. The acquisition of a suppressive phenotype by CD8^– DCs correlates with activation of the PI3K/Akt and noncanonical NF-B pathways. These data are the first to link TGF-β signaling with IDO in controlling spontaneous tolerogenesis by DCs.

	Introduction

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Murine dendritic cells (DCs)³ present Ag in an immunogenic or tolerogenic fashion, the distinction depending either on the occurrence of specialized DC subsets or on the maturation or activation state of the DC. Although DC subsets may be programmed to direct either tolerance or immunity, appropriate environmental stimulation will result in complete flexibility of a basic program. Using splenic CD8^– and CD8⁺ DCs that mediate the respective immunogenic and tolerogenic presentation of self-peptides, we have previously shown that the activities of both subsets can be altered by regulatory (T_reg) or effector T cells. Otherwise immunogenic CD8^– DCs became tolerogenic upon B7-1 ligation by soluble or cell-bound CTLA-4, a maneuver initiating IDO-dependent tryptophan catabolism (1, 2). In contrast, CD28 ligation of B7-1/2 on IDO-competent CD8⁺ DCs made these cells capable of immunogenic presentation (3). Although T cell control may result in functional plasticity of the DC, the mechanisms underlying default tolerogenesis by CD8⁺ DCs have been unclear (4).

Among the environmental factors that contribute to tolerogenesis in adaptive immunity, TGF-β is a most important immunoregulatory cytokine (5). Produced by activated T cells and acting through TGF-β type I (TGF-βRI) and type II (TGF-βRII) receptors, this cytokine initiates Smad-dependent and -independent pathways of signal transduction (5). Its pleiotropic functions affect several cell types, including APCs, mast cells, NK, CD4⁺, CD8⁺ T, and NKT cells, where it regulates differentiation, survival, and proliferation (6). Besides inhibiting differentiation and effector function of T cells (7), TGF-β contributes to CD4⁺ lineage commitment to a T_reg or Th17 phenotype (8).

Scant information is instead available on the early effects of TGF-β that, by directly targeting DC subset activation and Ag presentation, may bias the subsequent response in favor of immunity or tolerance. In the present study we provide evidence, and mechanistic insight, for a role of TGF-β in maintaining the basic tolerogenic program of IDO-competent CD8⁺ DCs and in converting otherwise immunogenic CD8^– DCs into tolerogenic cells.

	Materials and Methods

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Mice and reagents

Female DBA/2J (H-2^d) mice were obtained from Charles River Breeding Laboratories. Recombinant human TGF-β1 was purchased from R&D Systems. Anti-murine TGF-β IgG1 mAb (1D11) that neutralizes all TGF-β isoforms was used (9), and the isotype control, 13C4, was from Genzyme. The ALK-5 (activin receptor-like kinase 5) inhibitor SB-431542 was from Sigma-Aldrich, and LY294002, which inhibits PI3K phosphorylation, was from Cell Signaling Technology. The P815AB (amino acid sequence LPYLGWLVF) peptide was synthesized and purified as described (4). All in vivo studies were done in compliance with National (Italy) and Perugia University Animal Care and Use Committee guidelines.

DC preparations and treatments

DCs were prepared and fractionated according to CD11c/CD8 expression using positive selection columns in combination with CD11c and CD8 MicroBeads (Miltenyi Biotec) as previously described (4). DCs were exposed to 20 ng/ml TGF-β for 24 h at 37°C in the presence or absence of SB-431542 (10 µM) or LY294002 (50 µM) added 1 h before the cytokine. No differences occurred in IL-6 production between CD8⁺ and CD8^– DCs treated or not treated with TGF-β. For TGF-β neutralization, DCs were incubated in vitro with 1D11 mAb (20 µg/ml) or mice were treated twice with 0.5 mg of the same mAb per mouse 24 h before and after immunization in the skin test assay.

Immunization and skin test assay

For immunization, a total of 3 x 10⁵ peptide-pulsed CD8^– DCs (majority population) was injected either alone or in combination with a minority fraction (3–5%) of CD8⁺ or conditioned CD8^– DCs. A skin test assay was used for measuring class I-restricted, delayed-type hypersensitivity responses to synthetic peptides (4). Results were expressed as the increase in footpad weight of peptide-injected footpads over that of vehicle-injected counterparts. Data are the mean ± SD for at least six mice per group. Statistical analysis was performed using Student’s paired t test by comparing the mean weight of experimental footpads with that of control counterparts.

Small interfering RNA (siRNA) synthesis and transfection, ELISA, and Western blotting

The siRNA sequences and transfection were as described (10). An alternative sequence of Indo siRNA (sequence: 5'-UCAAGGAUCCUUCUAGAACtt-3'; alternative sequence: 5'-GUUCUAGAAGGAUCCUUGAtt-3') was used to check for possible off-target effects of Indo silencing, and none were found. TGF-β was measured by a commercially available ELISA kit (Promega). In Western blot analysis, IDO expression was investigated as previously described using a specific Ab (2), and anti–β-tubulin (Sigma) was used as a loading control. Cytosolic and nuclear extracts were prepared as previously described (10), and p52 nuclear localization was analyzed using anti-NF-B2 p100/p52 (Cell Signaling Technology) and anti-actin (Sigma) as a loading control. On studying IB kinase (IKK) and Akt phosphorylation, immunoblotting was performed by sequential exposure to anti-phospho-IKK (Ser¹⁸⁰)/-IKKβ (Ser¹⁸¹) and anti-IKK or to anti-phospho-Akt (Ser⁴⁷³) and anti-Akt Abs, respectively (2). All of these Abs were from Cell Signaling Technology.

	Results

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IDO and TGF-β are necessary for spontaneous tolerogenesis by CD8⁺ DCs

The spleens of DBA/2 mice contain functionally distinct DC populations. The CD8^– majority fraction (90%) mediates immunogenic presentation of the synthetic tumor/self nonapeptide P815AB, while a CD8⁺ minority fraction (10%) initiates durable Ag-specific anergy upon transfer into recipient hosts (11). The default tolerogenic potential of CD8⁺ DCs is such that as few as 3% CD8⁺ DCs admixed with CD8^– DCs are sufficient to inhibit the induction of immunity to P815AB by the latter cells when Ag-specific skin test reactivity is measured 2 wk after cell transfer. We preliminarily tested whether IDO is necessary for default tolerogenesis by CD8⁺ DCs. Transfection of the CD8⁺ fraction with Indo-specific siRNA caused loss of suppressive activity upon cotransfer with peptide-pulsed CD8^– DCs (Fig. 1A), demonstrating a requirement for IDO in the basic functional program of CD8⁺ DCs.

View larger version (21K): [in this window] [in a new window]   FIGURE 1. TGF-β is required for default suppression by CD8+ DCs. A, P815AB-pulsed CD8– DCs or a mixture of CD8– DCs and 3% CD8+ DCs were transferred into recipient mice to be assayed for skin test reactivity at 2 wk. The CD8+ DC fraction was used as such or after Indo silencing by siRNA. CD8+ DCs treated with negative control (nc) siRNA were included as a control. *, p < 0.001, experimental vs control footpads. One experiment is representative of three. B, Twenty-four hours before and after immunization with P815AB-pulsed DCs, mice received anti-TGF-β Ab or isotype control (0.5 mg/mouse) or were left untreated. Groups were injected with CD8– DCs either alone or combined with a minority fraction of CD8+ cells, and skin test reactivity was assayed at 2 wk. *, p < 0.001, experimental vs control footpads in one of three experiments. C, TGF-β was measured in unstimulated culture supernatants at different times. Data are means ± SD in one experiment representative of four. Inset, IDO protein expression by freshly harvested CD8+ and CD8– DCs. D, A mixture of P815AB-pulsed CD8– DCs and 3% CD8+ DCs were transferred into recipient mice to be assayed for skin test reactivity at 2 wk. The CD8+ DC fraction was used as such or after 24-h incubation with SB-431542 or anti-TGF-β, and 0.1% DMSO (vehicle) and isotype control were included as controls. *, p < 0.001, experimental vs control footpads (one experiment representative of three). E, Sorted CD8+ DCs were exposed to anti-TGF-β or isotype control for 4 or 20 h. At the end of the culture, mRNA levels of Indo were quantified by real-time PCR using Gapdh normalization. Data (means ± SD of three experiments) are presented as normalized transcript expression in the samples relative to normalized expression in the respective control cultures, i.e., cells unexposed to anti-TGF-β but maintained in medium alone (fold change = 1; dotted line).

Because DCs can be triggered to produce TGF-β under particular environmental conditions (15), production of TGF-β was measured in supernatants from unstimulated cultures of CD8^– and CD8⁺ DCs. At 32 h of culturing, CD8⁺ DCs, but not their CD8^– counterparts, released significant amounts of TGF-β (Fig. 1C). To clarify whether the cytokine might act in an autocrine fashion, we examined development of skin test reactivity in hosts transferred with a mixture of CD8^– cells and 3% CD8⁺ DCs. The latter cells were either untreated or treated in vitro with a specific inhibitor of the serine/threonine kinase ALK-5 (activin receptor-like kinase 5) receptor for TGF-β (SB-431542) or with TGF-β-neutralizing Ab (Fig. 1D). Both approaches blocked the basic tolerogenic program of CD8⁺ DCs. Also, Indo quantitative expression was assessed by real-time PCR in CD8⁺ DCs treated in vitro with TGF-β-neutralizing Ab or control Ab. A decrease in gene transcriptional activity, although observable at 4 h, was most evident at 20 h of incubation (Fig. 1E).

Thus, the default suppressive program of CD8⁺ DCs requires not only Indo expression but TGF-β, which acts on CD8⁺ DCs in an autocrine fashion.

TGF-β confers IDO competence and tolerogenic activity on CD8^– DCs

Next, we examined whether TGF-β would affect the default immunogenic function of CD8^– DCs, which are also characterized by functional plasticity in the same setting of peptide-specific skin test responses (4). When otherwise immunogenic CD8^– DCs were admixed with a minority fraction (5%) of the same cells pretreated with TGF-β, induction of skin test reactivity was abolished (Fig. 2A). Moreover, the suppressive effect conferred by TGF-β on CD8^– DCs was lost upon the silencing of Indo in concurrence with cytokine exposure. Indo silencing, however, did not completely restore the response, and this could be due to the fact that the efficiency of Indo silencing is 60% at 24 h and >95% at 48 h. Real-time PCR (at 20 h; Fig. 2B) and immunoblot (at 48 h; Fig. 2C) analyses revealed significantly increased expression of IDO in CD8^– DCs exposed to TGF-β in vitro. Of interest, Fig. 2D provides direct evidence that, in accordance with previously published data, CD8⁺ but not CD8^– DCs express enzymatically functional IDO spontaneously. Also shown in Fig. 2D is the ability of externally added TGF-β to initiate tryptophan catabolism by CD8^– DCs. Taken together, these data indicated that TGF-β may activate Indo transcription and turn CD8^– DCs from immunogenic into tolerogenic cells.

View larger version (29K): [in this window] [in a new window]   FIGURE 2. TGF-β operates a phenotype switch in CD8– DCs via IDO induction. A, P815AB-pulsed CD8– DCs were admixed with a 5% fraction of differently treated CD8– DCs and then injected into recipient mice to be assayed for skin test reactivity at 2 wk. Specific Indo gene silencing or control siRNA treatment were performed 5 h before TGF-β (18-h exposure). *, p < 0.001, experimental vs control footpads (one of three experiments). B and C, CD8– DCs were exposed for various lengths of time to TGF-β. mRNA levels of Indo were quantified by real-time PCR (B) as in Fig. 1E. IDO protein expression was assayed by immunoblot analysis (C). Blots were stripped and reprobed with anti–β-tubulin Ab. Data (means ± SD from three experiments) were analyzed by scanning densitometry and are presented as normalized protein expression in the samples relative to normalized expression in the respective control cultures, i.e., cells unexposed to TGF-β but maintained in medium alone (fold change = 1; dotted line). D, Spontaneous functional IDO expression by CD8+ and not CD8– DCs cultured (2 x 106/ml) with 150 µM tryptophan for 5 h and the effect of externally added TGF-β (18-h incubation). Data are means ± SD from three independent experiments.

TGF-β activates noncanonical NF-B in CD8^– DCs

Noncanonical NF-B is necessary for induction of Indo transcription (10, 16). Of the two IKK complex catalytic subunits, IKK and IKKβ, the latter is indispensable in the canonical, proinflammatory pathway of NF-B activation, whereas IKK is pivotal in the noncanonical activation leading to Indo transcription (10, 17). IKK is phosphorylated by the NF-B-inducing kinase (NIK) and operates the processing of p100 into p52 with the consequent formation of p52-RelB dimers, which translocate into the nucleus and activate gene transcription.

To investigate whether TGF-β-dependent induction of IDO required noncanonical NF-B signaling, we examined tolerogenicity by TGF-β-converted CD8^– DCs with silenced Nik or IKK expression. In the same experimental design as in Fig. 3A, using the siRNA-treated cells as a minority fraction combined with the immunogenic majority component, we found that NIK and IKK, but not IKKβ, were required for induction of the suppressive phenotype by TGF-β in CD8^– DCs (Fig. 3A).

View larger version (20K): [in this window] [in a new window]   FIGURE 3. Activation of noncanonical NF-B by TGF-β in CD8– DCs. A, P815AB-pulsed CD8– DCs were admixed with a minority fraction (5%) treated in vitro with siRNAs before TGF-β addition and injection into recipient mice to be assayed for skin test reactivity at 2 wk. Nc, negative control. *, p < 0.001, experimental vs control footpads in one of three experiments. B, CD8– DCs were purified and stimulated with TGF-β. At the indicated times, cytosolic and nuclear extracts were obtained for Western blot analyses with specific Abs for phospho-IKK (Ser180)/phospho-IKKβ (Ser181) or NF-B2 p100/p52, respectively. Anti-IKK and anti-actin Ab were used as a loading control. Time 0 represents control cells unexposed to TGF-β (fold change = 1). Results are ratios (indicated) between scanning densitometry data (means ± SD from three experiments).

TGF-β signaling in CD8^– DCs involves PI3K activity and Akt phosphorylation

Smads are a group of signaling mediators responding to members of the TGF-β superfamily. In addition, signal transducers have been identified that act as mediators of Smad-independent signaling, including the PI3K/Akt pathway, which might link TGF-β (18) with noncanonical NF-B (19). We investigated the effect of the PI3K specific inhibitor LY294002 on the tolerogenic potential induced by TGF-β in CD8^– DCs in the skin test assay. The minority population was incubated with LY294002 for 1 h before overnight stimulation with TGF-β. After mixing with the immunogenic fraction and cell transfer, skin test reactivity was measured at 2 wk in recipient hosts (Fig. 4A). PI3K inhibition ablated TGF-β effects, thus preventing the onset of a tolerogenic phenotype. Akt phosphorylation (Fig. 4B) and NF-B p52 nuclear localization (Fig. 4C) were assayed by immunoblotting. Akt phosphorylation was found to occur at 5–10 min of TGF-β exposure, and p52 nuclear localization was decreased in the presence of the PI3K inhibitor, LY294002, at 20 min of TGF-β stimulation. Thus, in this cell system TGF-β activates PI3K/Akt and noncanonical NF-B pathways, the latter acting downstream in the signaling cascade.

View larger version (12K): [in this window] [in a new window]   FIGURE 4. Involvement of PI3K/Akt pathway in the function of CD8– DC treated with TGF-β. A, A minority fraction of CD8– DCs was left untreated or incubated with LY294002 for 1 h, stimulated overnight with TGF-β, and admixed with the majority fraction of the same cells. All cells were pulsed with P815AB peptide before administration in vivo. Peptide-specific skin test reactivity was measured at 2 wk. *, p < 0.001, experimental vs control footpads in one of three experiments. B, CD8– DCs were cultured at 1 x 106/ml with TGF-β for different times. Cell lysates were subjected to Western blot analysis with a specific anti-phospho-Akt (Ser473) Ab. Blots were stripped and reprobed with anti-Akt Ab. Scanning densitometry data (ratios; means ± SD from three experiments) are shown in which time 0 indicates cells unexposed to TGF-β (fold change = 1). C, CD8– DCs were left untreated or incubated with LY294002 for 1 h and then stimulated with TGF-β. At the indicated times, nuclear extracts were obtained for Western blot analysis with specific Ab to NF-B2 p100/p52. Anti-actin Ab was used as a loading control. All results are representative of three independent experiments.

	Discussion

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We found that TGF-β acts on DCs through a pathway involving PI3K/Akt phosphorylation and noncanonical NF-B activation. This pathway most likely acts at both the transcriptional (Fig. 2B) and the posttranslational (Fig. 1C) levels. Additionally, in other experimental systems the following was noted: 1) activation of the PI3K/Akt system was observed in the angiogenic response to TGF-β in mouse capillary endothelial cells (23); 2) Akt promotes the processing of p100 into p52 and therefore regulates noncanonical NF-B activity (19); and 3) Indo transcription in mouse plasmacytoid DCs is strictly contingent on noncanonical NF-B (10). Furthermore, a recent report indicates that spontaneous renal allograft acceptance correlates with TGF-β and IDO expression by regulatory DCs (24). Also, apoptosis-induced DC suppression correlates with the combined effects of TGF-β, IFN-, and IDO in another setting (25). Finally, Helicobacter pylori-induced IDO activity is critically affected by TGF-β polymorphism (26). In the human system, TGF-β produced by human CD8⁺ T_reg cells is involved in the induction of tolerogenic mechanisms by plasmacytoid and myeloid DCs, and IDO has a role in plasmacytoid but not myeloid DC function (27).

In conclusion, the present study suggests a new and general function of TGF-β and the PI3K/Akt system in initiating or reinforcing IDO expression by DCs at the interface between innate and adaptive immunity. Autocrine and paracrine TGF-β signaling in DCs could be critical in the balance between immunity and tolerance by promoting an early regulatory environment and spreading tolerance from one cell population to another, according to a pattern expressively indicated as infectious tolerance in acquired immunity.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Italian Association for Cancer Research (to P.P.).

² Address correspondence and reprint requests to Dr. Maria L. Belladonna or Dr. Paolo Puccetti, Department of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia 06126, Italy. E-mail addresses: laurabell{at}tin.it and plopcc{at}tin.it

³ Abbreviations used in this paper: DC, dendritic cell; IKK, IB kinase; NIK, NF-B-inducing kinase; siRNA, small interfering RNA; T_reg, regulatory T cell.

Received for publication July 16, 2008. Accepted for publication August 18, 2008.

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