Tolerogenic dendritic cells in health and disease: friend and foe!

ARTICLE

Auteur(s) : Henric S. Adler, Kerstin Steinbrink

Department of Dermatology, University of Mainz, Germany

accepté le 10 Juillet 2007

Introduction: immune defence vs. immune tolerance

As professional antigen presenting cells, dendritic cells (DCs) are a central element in fulfilling these tasks. They take up, process and present antigens in concert with costimulatory molecules and cytokines to direct an immune response. DCs are continuously produced from hematopoetic stem cells and are widely distributed as immature DCs in both lymphoid and non-lymphoid tissues. DCs reside at body surfaces, especially the skin, the airways, in the interstitial spaces of many organs, in the blood, and afferent lymphatics [1]. By expressing molecular components of intercellular junctions, DCs may insinuate through tight epithelia, while extending their processes into the environment to capture proteins without breaking the epithelial barrier [2]. Thus, DCs can be considered as specialized sentinels to scrutinize for pathogens, they integrate and propagate information concerning homeostatic/steady state and inflammatory/infectious situations, respectively, and control the ensuing responses.

The role of DCs for innate and adaptive immune defence has been reviewed thoroughly elsewhere [1, 3, 4] and will be considered only briefly here. The decision to initiate an immune response and its quality are largely dependent on “danger” signals associated with the presence of distinct pathogen challenges (figure 1). The expression of Toll-like receptors (TLR) and molecules such as C-type lectins, mannose receptors or intracellular nucleotide-binding-oligomerization domains (NOD) enables DCs to recognize conserved pathogen associated molecular patterns (PAMP) like yeast or bacterial glycoproteins, dsRNA, and CpG-DNA, respectively, and to induce a balanced innate and adaptive response [4-6].

The former concept of “discrimination between self and non-self” has been expanded by the theory of an immune system which discrimitates the steady state situation, with absence of pathogens, from a situation which is identified as a threat, requiring immune defence mechanisms. This idea has been introduced as the “danger model” [7]. In steady state conditions, where there is no threat but a multitude of antigens derived from body tissues and innocuous agents, the second task of the immune system is predominant: to prevent self-destructive autoimmunity and unnecessary immune activation. Two safety concepts have evolved to ensure this: central and peripheral tolerance.

Central tolerance

Peripheral tolerance

• (i) An antigen that does not reach secondary lymphoid tissues in minimum doses for a suffiently long period of time to be appropriately presented by APCs is immunologically ignored.
• (ii) Antigen which is constantly present in the lymphoid tissue or reaches it in excessive amounts and is presented for extended periods of time, leads to peripheral deletion of T cells.
• (iii) Presented antigen, which leads to TCR stimulation without sufficient positive costimulatory signalling by DC, leads to anergy, characterized by impaired proliferation and effector functions in response to further stimulation. (iv) Generation of regulatory T cells (Treg) can either take place in the thymus – as for naturally occuring CD4⁺CD25⁺FOXP3⁺Treg [8, 10] – or in the periphery e.g. by tolerogenic DCs (tDCs) – as for induced Treg (iTreg) (see below). Induction of anergy (iii) and suppression (iv) will be discussed in more detail below in the light of the involvement of tolerogenic DCs (tDC).

Human and murine DC

Development of cell culture methods since the 1990s has allowed for the generation of larger quantities of DCs of murine and human origins for detailed morphological and functional analysis [14-26]. In vitro, the most accessible human DC types are monocyte-derived DCs (moDC). These cells can be generated by culture of CD14⁺ precursor cells with GM-CSF and IL-4 or IL-13 [26-32]. This results in an immature DC phenotype, which is defined by strong antigen uptake and low costimulatory capacity. Further stimulation with inflammatory cytokines (e.g. IL-1β, TNF-α, IL-6 and PGE₂) [24], by-products of tissue damage or agents representing PAMPs, which are recognized by Toll like receptors (TLR), leads to distinct mature phenotypes with certain functional specializations [33-35]. Alternatively, DCs can be generated in vitro from CD34⁺ precursor cells [21, 36-40].

Maturation of DCs is accompanied by (i) increased formation of stable MHC-peptide complexes [6, 41-43]; (ii) higher expression of costimulatory molecules (B7- and TNFR-families) [44-48]; (iii) new synthesis of cytokines that influence T cell proliferation and polarization [49, 50]; and (iv) altered expression of chemokine receptors and production of chemokines that allow for the movement of DCs into lymphatic vessels and lymphoid organs in vivo and attraction of T cells respectively [51-54] (figure 2). But DC maturation may also occur in the absence of infection during such strong T cell immune responses as in conditions of graft versus host disease [55], contact allergy [56], and autoimmunity [57].

The function of immature DCs in the concept of steady state peripheral tolerance

The normal processes of cellular turnover provide tissue resident iDCs with a constant supply of self antigens for processing and presentation. Experimental evidence in vivo shows that antigens from a diversity of cell types such as leucocytes, endocrine and epithelial cells from the intestine and the skin can be transferred to DCs constitutively. This has been shown by proving the presence of cell type specific protein markers (e.g. keratin, melanin) in stDCs [61]. Besides the capture of soluble proteins via the expression of multilectin receptors like MMR (macrophage mannose receptor) or DEC-205, one important mechanism seems to be the efficient uptake of cellular constituents of dying cells through apoptotic bodies [61-66]. Recognition of apoptotic cells is mediated by a series of apoptotic cell-associated molecular patterns (ACAMP) that are recognized by DC [62, 67]. Receptors involved include scavenger receptors like CD36, the α_v-integrin chain, complement receptors for C1q and iC3b, the integrin associated protein CD47 and others [63, 66, 67]. Several studies have shown that under non-infectious conditions immature DCs, which have internalized early apoptotic cells, fail to upregulate MHC and costimulatory molecules. In addition, these iDCs have a reduced ability to secrete proinflammatory cytokines and to produce the immunosuppressive cytokines IL-10 or TGF-β [66]. This sustained immature phenotype prevents activation and polarization of T cells reactive against the antigens of apoptotic cells presented, and can contribute to peripheral tolerance.

Internalization of apoptotic cell fragments can lead to migration towards proximal secondary lymphoid tissue in vivo. This involves a switch in chemokine receptor expression from homing to inflamed tissue versus a lymph node homing pattern, by down regulating CCR5 and upregulating CCR7 [68]. This may be mediated, in part, by opsonizing apoptotic cells with iC3b [69]. Migratory iDCs isolated ex vivo exhibit a certain level of surface MHC expression, T cell costimulatory and adhesion molecules, IL-10 production, low levels of proinflammatory cytokines, but the virtual absence of IL-12p70 synthesis [61, 63, 70].

It is still an open question whether these migratory stDCs, sometimes also called “semimature DCs” [59], die rapidly in vivo with the respective antigens then being transferred to lymph node resident DCs, or if the migratory stDCs are themselves the inducers of tolerance. By analysis of DC-T cell interaction in vivo using real-time two-photon-microscopy, one group has shown that the contacts of CD8⁺ T cells in tolerogenic situations are brief and T cells remain motile, establishing serial contacts with multiple lymph node resident DCs, whereas during induction of immunity, T cells stop moving after 15-20 h and establish prolonged interaction with DCs [71]. Similar results were obtained for CD4⁺ T cells in another study [72].

Briefly summarized, migratory DC during steady state (figure 1) have distinct morphological and functional characteristics with reduced proinflammatory and costimulatory potential and form brief serial interactions with T cells in vivo. Further experimental evidence for the function and impact of stDCs for tolerance induction in vivo has been reviewed in detail by Steinman et al. [61, 73].

Induction of tolerogenic DCs in vitro

A major part of these strategies and the respective experimental results will be discussed in further detail below.

iDCs as a tool to induce regulatory T cells

In vitro generated immature monocyte-derived DCs have been shown to induce antigen specific inhibition of effector T cell function in vivo after injection in healthy human subjects. A single injection of immature DCs [iDC) pulsed with influenza matrix protein (MP) and keyhole limpet hemocyanin (KLH) led to the inhibition of MP-specific CD8⁺ T cell effector function. MP-specific CD8⁺ T cells, as identified by tetramer staining, were expanded in those individuals but showed reduced IFN-γ production and lacked killer activity as compared to pre-immunization. Notably, IL-10 producing MP-specific cells appeared after immunization with iDC, which might represent Tr1 type regulatory T cells [91] (table 2).

Murine bone marrow-derived iDCs generated CD25⁺ Tr1-like regulatory T cells, which suppressed enteroantigen-induced T cell proliferation in vitro in an IL-10-mediated cell contact-independent manner. Purified preparations of these Tr1-like cells generated in vitro protected from enteroantigen-reactive disease in a murine colitis model in vivo, after injection. CD4⁺ T cells of protected mice secreted higher levels of IL-10 and lower levels of IFN-γ after antigen specific stimulation [92]. Other work has shown that repetitive injection of iDCs triggered the expansion of an IL-10-producing T cell population, which did not express FOXP3 [93]. Adoptive transfer of this cell population protected mice from collagen-induced arthritis. This was associated with local IL-10 production and an attenuation of T and B cell responses, as measured by diminished cytokine production ex vivo and reduction of the disease-associated bCII-specific antibody in the sera of treated mice (table 2).

Table 1 Features of human monocyte derived mature and tolerogenic DCs

IL-10 modulated DCs

In contrast, if DCs were allowed to differentiate for 5 to 7 days and IL-10 was added at this time point together with a maturation stimulus, such as a mix of inflammatory cytokines [100] or LPS [101], the DC phenotype was preserved, yet maturation-induced upregulation of MHC molecules, costimulatory molecules, and adhesion molecules was prevented and the LPS-induced production of cytokines was impaired (table 1). Importantly, in contrast to iDCs, IL-10DCs do not display functional plasticity and are resistant to further maturation. IL-10DCs show high expression of some members of the B7 family (table 2), the inhibitory molecules ILT2 and ILT3, and are low secretors of inflammatory cytokines [HS Adler, unpublished results, references [101-104] and table 1]. IL-10 also has a strong impact on the maturation-induced switch of chemokine receptor expression. IL-10DCs express low levels of the lymph node targeting CCR7, yet retain cell surface expression of inflammatory CCR1, CCR2, CCR3, CCR5 (HS Adler, unpublished results, ref [105] and table 1). CCR1, CCR2 and CCR5 have been shown to be functional decoys, which may act as molecular sinks and scavengers for inflammatory chemokines [105].

IL-10DCs have a dramatically reduced capacity to stimulate primary T cell proliferation, prevent activation of primed or naive T cells by anti-CD3 and induce antigen-specific anergy in primed and naive CD4⁺ and CD8⁺ T cells in a variety of experimental setups [101, 106-112] Anergized CD4⁺ and CD8⁺ T cells had impaired effector functions, reduced IFN-γ production, and melanoma tyrosinase-specific CD8⁺ T cells failed to lyse target cells. Antigen-specific anergy was broken by the addition of high amounts of exogenous IL-2 [109, 110].

Notably, anergic T cells, generated by culture with IL-10DCs, display suppressor activity and can thus be considered as a population of induced regulatory T cells (iTreg). These CD4⁺ or CD8⁺ iTregs suppressed proliferation, IL-2 and IFN-γ production of syngeneic effector T cells in a cell contact-dependent manner, independent from soluble factors such as IL-10 or TGF-β [113]. These iTreg displayed increased intracellular and extracellular expression of CTLA-4. Blocking of this molecule partially restored proliferation in suppressor assays, indicating an important role for CTLA-4 in the suppressor function of iTregs.

Suppressor function and anergy of iTregs are associated with a cell cycle arrest in the G₁ phase, mediated by high expression of the cyclin-dependent kinase (cdk) inhibitor p27^kip1. This prevents phosphorylation-induced degradation of Rb and cell cycle progress. Both IL-2 and anti-CTLA-4 led to decreased expression of p27^kip1 and loss of suppressor function in co-cultures [114].

Recently, we identified a distinct pattern of MAP kinase activation in iTreg generated by IL-10DC [115]. As compared to fully activated effector T cells, iTregs had diminished JNK activity and showed no induced activation of ERK. In contrast, the activity of MAP kinase p38 and its downstream effector kinases MAPKAP-K 2/3 were significantly increased during priming and restimulation of iTregs. The elevated activation of p38 proved to be critical for both, the induction and maintenance of anergy, controlled by the enhanced expression of p27^Kip1. Inhibition of p38 by the specific inhibitor SB203580 either during priming or restimulation of iTreg, resulted in loss of the anergic state, downregulation of p27^Kip1 expression, cell cycle progress and restored production of IL-2 and IFN-γ.

Furthermore, the antigen-specific suppressor function of iTreg was strictly dependent on p38 controlled cell cycle arrest and lost by treatment with SB203580.

For generation of iTregs by IL10-DCs, some surface molecules have been reported to be of particular relevance. B7-H1 is highly expressed on IL-10DCs (table 1) [108]. Blocking of this molecule on IL-10DCs strongly enhanced their stimulatory capacity on T cells in primary proliferation. If B7-H1 – PD-1 interaction was blocked at restimulation of T cells precultured with IL-10DCs, anergy was broken and proliferation restored [108].

These in vitro generated data for human IL-10-modulated DCs have been supported by experiments performed in the murine system in vitro and in vivo. In an OVA-specific allergy model, the treatment with OVA-pulsed IL-10-modulated BMDCs in prophylactic and therapeutic experiments resulted in strongly reduced OVA-specific T cell proliferation in vitro and significantly impaired DTH-reactions in vivo [116]. In a related model of murine OVA-induced asthma, treatment of mice with OVA-pulsed IL-10BMDCs prior to and during OVA/alum sensitization resulted in significantly impaired OVA-specific proliferation and cytokine production by lymph node cells. However, systemic (OVA-specific IgE) and local (airway eosinophilia) allergen responses remained unchanged [117] (table 2). The presence of a cell type similar to in vitro generated IL-10BMDCs was also shown in the spleen and lymph nodes of BALB/c and C57BL/6 mice in vivo and was significantly enriched in the spleen of IL-10 transgenic mice [118] (table 2).

In some experimental settings, human moDCs (phenotype, table 1) or murine BMDCs modulated with IL-10 plus TGF-β have been used. [119-121]. The experimental results suggest no basic differences in the ability of IL-10DCs and IL-10/TGF-β-DCs to efficiently generate iTregs (table 2).

Immunosuppressive agents targeting NFκB to generate tDCs

The immunomodulatory effect of IL-10 on murine bone marrow-derived iDCs is also mediated in part by suppression of the PI3K/Akt pathway and IκB kinase activity, both leading to reduced NFκB activation [129]. Further strategies, such as the use of IκB kinase- or NFκB inhibitors (see below), steroid hormones (see below), Vitamin C, Vitamin E [130], Vitamin D3 (see below) or neuropeptides [131-133] to generate tDCs, target this central regulatory pathway in DC maturation.

Direct targeting of NFκB to induce tDCs

In human moDCs, inhibition of NFκB by a pharmacological inhibitor (pyrrolidine dithiocarbamat, PDTC) prevented LPS-induced maturation, led to reduced expression of HLA-DR, costimulatory molecules and proinflammatory cytokines (table 1), and induced alloantigen specific anergy in T cells [139]. Another inhibitor of NFκB (Bay 11-7082), which has been shown to induce antigen-specific tolerance in vivo in mice by inducing IL-10 producing Treg [140], did not modify human moDCs in vitro. Other pharmacological substances that have been described to induce tDCs, at least in part, by targeting NFκB, include the tyrosine kinase inhibitor Imatinib (human moDC) [141], the immunosuppressive drug FK778 (human moDC) [142] and cyclosporin A (murine BMDC) [143], and dexamethasone (murine DC line) [144] (murine BMDC) [145].

Glucocorticosteroid modulated tDCs

Hydrocortisone (HC) has less potency than dexamethasone. In one report, allergen-pulsed human HC-treated moDCs of atopic individuals (HC-DCs) were compared to IL-10DCs [112]. IL-10DCs inhibited the production of Th1 and Th2 cytokines in naive, but not memory T cells, whereas HC-DC-priming inhibited IFN-γ, but not IL-4 or IL-5 production in naive T cells upon restimulation with allergen-pulsed mature DCs.

The effect of dexamethasone on DC function has also been addressed in murine DC lines [144, 155-157], murine LCs [158, 159], murine spleenic DCs [160] and BMCDs [145, 147, 154, 157, 161-164] (table 2). Dexamethasone treatment of murine BMDCs prior to LPS stimulation led to maturation resistance [145, 157, 162, 163]. Multiple rounds of restimulation with LPS-DEX-BMDCs induced a population of IL-10-producing IL-4^-/IFN-γ^- CD4⁺ T cells [157, 161]. In a murine transplantation model, LPS-DEX-BMDCs induced antigen specific T cell anergy and prolonged survival of a completely MHC-mismatched heart allograft more efficiently than immature BMDCs [162] (table 2).

The generation of functional Treg, induced by dexamethasone-treated matured DCs, has been shown by use of a newly established murine immature DC line (SP37A3) [155]. Maturation is induced by GM-CSF plus the proinflammatory cytokines IL-1β and TNF-α or LPS, respectively. Addition of dexamethasone resulted in tolerogenic DCs, expressing diminished levels of MHC II and costimulatory molecules, and reduced levels of mRNA for CD83, OX40L and the cytokines IL-1β, IL-6, and IL-12, whereas mRNA for IL-1RA was drastically enhanced. Priming of T cells with these DCs induced a population of Treg, which suppressed antigen-specific T cell proliferation in vitro [155].

1,25(OH)₂ Vitamin D3-modulated tDCs

Stimulation of T cells with tolerogenic 1,25(OH)₂D₃-treated matured DCs resulted in reduced primary proliferation and IFN-γ production during primary activation [166, 170, 171, 173, 177]. When restimulated, T cells primed with 1,25(OH)₂D₃-treated moDCs showed upregulation of CD152 (CTLA-4), impaired proliferation and IFN-γ production, which could not be rescued by high amounts of exogenous IL-2. One report states that this T cell anergy is antigen-unspecific, as restimulation with mature DCs derived from a second donor, unrelated to the DCs used for priming, also resulted in T cell hyporesponsiveness [169] – in striking contrast to T cell anergy induced by IL-10DCs [100, 110, 113]. Anergic T cells, induced by immature 1,25(OH)₂D₃ treated moDCs, express enhanced levels of FOXP3 and display antigen unspecific suppressor activity. The tolerogenic effects of 1,25(OH)₂D₃ and its analogues have also been observed on murine DCs in vitro [145, 178-181] and in vivo [182, 183] (table 2).

Upregulation of IDO expression in tDCs

Tolerogenic DC in vivo and therapeutical impact: friend or foe?

Tumor-derived factors modulate DCs

UV radiation impairs DC function

Two different animal models were used to study the effects of UVR, the “acute low dose model” and the “high dose model”. Low dose UVB induced inhibition of the local sensitisation phase of CHS response to a hapten [214]. High dose UVB irradiation induced inhibition of the systemic sensitization phase of CHS and DTH when antigen is applied at distant, non-irradiated skin. Low dose UVR led to the development of tolerance, which correlated with functionally impaired DCs in non-draining lymph nodes. This systemic suppression of DC function and induction of hapten tolerance was dependent on IL-10 production by keratinocytes in the epidermis [215]. Adoptive transfer of UV-induced suppressor T cells in a transgenic model revealed that induction of hapten-specific tolerance was mediated via Fas/Fas-ligand induced cell death of DCs in the recipients, which could be prevented by IL-12 [216]. The Treg population acting on DCs was further characterized as CTLA-4⁺ secretors of high amounts of IL-10, TGF-β and IFN-γ, but low levels of IL-2 and no IL-4. CTLA-4 expression proved to be functionally relevant as blockage of CTLA-4⁺ prevented induction of tolerance in vivo and prevented IL-10 secretion in vitro [217]. Thus, at least two mechanisms seem to contribute to UV-induced tolerance: one involving the generation of Tr1-like regulatory T cells, possibly via IL-10 modulation of DC function and a second relying on apoptosis of DCs caused by an induced IL-10 secreting CTLA-4⁺ Treg population [209, 210, 218].

Modulation of DC function by commensals and pathogens

A variety of pathogens have developed strategies to weaken host immune defences, especially by modifying DC function, thus generating a tolerogenic DC phenotype (figure 2) and impairing the resulting pathogen-specific immune response.

Herpesviridae like human cytomegalovirus (HCMV) [223, 224], murine CMV [225] and Herpes simplex virus 1 [226] reportedly inhibit DC functions. In the case of HCMV, production of the viral homologue of IL-10 (vIL-10) has a dramatic impact on the activation of STAT3, expression of costimulatory molecules and proinflammtory cytokines in human DCs comparable to the effect of human IL-10 [224]. This strategy of vIL-10 production has also been developed by a member of the Parapoxviridae, Orf virus, which induces cutaneous lesions in sheep goats and humans [227].

In HIV infection, the number of myeloid DCs and plasmacytoid DCs is reduced and their capacity to stimulate T cell proliferation is impaired, in part due to defective expression of costimulatory molecules [228, 229]. Lymph node DCs of acutely HIV-infected patients expressed reduced amounts of CD80 and CD86 [230]. The virus encoded protein Vpr appears to act on the expression of CD80, CD83, CD86 at the transcriptional level, and leads to an enhanced IL-10/IL-12 ratio in HIV-infected DCs [231]. Endogenously expressed HIV-encoded Nef in iDCs uncouples cytokine and chemokine production from maturation-induced expression of costimulatory molecules and thus allows the attraction of T cells for virus spread without subsequent appropriate activation of T cells [232]. Recently, it has been shown that mDCs generated from HIV-1 viremic individuals were substantially impaired in their ability to secrete IL-12 and to prime the proliferation of autologous NK cells, which in turn failed to produce adequate amounts of IFN-γ [233].

In helminthic infections, chronic immune activation results in hyporesponsiveness and anergy of T cells and an increase of Treg [234]. The inhibition of DC maturation and function appears to play an important role, and IL-10-modulation of DCs has been reported previously for helminthic infections [235, 236]. Furthermore, an increase of IL-10 and/or TGF-β production has been observed in vivo in humans and in baboons infected with helmiths, leaving the possibility that this might contribute to a tolerizing phenotype of DCs [237, 238].

What’s up with “mature” DCs inducing tolerance?

In detail: murine TNF-α-matured BMDCs induced antigen-specific protection from experimental autoimmune encephalitis (EAE) in mice [243]. In view of the 3 categories of signals (TCR-mediated, costimulatory molecule-mediated, cytokine-mediated) required for optimal priming and shaping of effector T cell responses, two signals (high MHC expression and high expression of costimulatory molecules) are provided by TNF-α-matured DCs, whereas signal 3 – the production of proinflammatory cytokines is severely impaired. Though TNF-α is part of well defined maturation protocols for human DCs [24], its use as a single maturation stimulus in the murine system is not sufficient to induce a fully mature DC phenotype. Some authors prefer the term “semi-mature” for this state [59]. Therefore these DCs meet the definition of tDCs and should not be called “mature” as defined above. In another model, costimulatory competent, CD40-deficient DCs are unable to prime CD4⁺ or CD8⁺ T cell responses in mice in vivo [240]. In this setting, the lack of one important member of the TNFR family of costimulatory molecules led to severely impaired cytokine production (i.e. IL-12) by DCs, thus, these DCs do not meet the above criteria for “mature DCs”. Interestingly, CD40/CD40L-mediated signal transduction seemed to be essential in this model as compared to IL-12 production itself, since IL-12 p40^–/– mice show normal levels of T cell activation. Murine DCs of genetically modified mice (TLR4^–/– or MyD88^–/–) exposed to endogenous levels of inflammatory mediators in vivo, were unable to prime T cell responses, although they showed features of conventional maturation and stimulated T cell proliferation in a comparable way as wild type DCs matured by TLR-ligands. Importantly, these indirectly activated DCs also lacked IL-12 production and primed for neither IL-4, nor IFN-γ production.

But in one aspect mature DCs are indeed involved in controlling tolerance, as mature DCs are able to expand functional CD4⁺CD25⁺FOXP3⁺ Treg [245, 246]. These Treg retain the ability to suppress conventional T cell functions as determined by proliferation and cytokine production. But “expansion” is not “generation” and thus mature DCs can not – referring to currently available data – be considered as tolerogenic DCs.

The characteristics of tolerogenic DCs: what do they have in common?

Future perspectives

Future research needs to address further refinement and adaption of current protocols for the respective therapeutical application and to compare the functional efficacy of the diverse populations of tDCs (table 1 and figure 2) for special applications, also including the analyses of the modes of action (apoptosis, induction of anergy and/or regulatory T cells). This would allow for the streamlined introduction of safe and more efficient new immunological therapies by use of tDCs.

Acknowledgements

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