Open Access

Role of dendritic cells in the induction of regulatory T cells

Cell & Bioscience20111:20

https://doi.org/10.1186/2045-3701-1-20

Received: 31 January 2011

Accepted: 24 May 2011

Published: 24 May 2011

Abstract

Dendritic cells (DCs) play a key role in initiating immune responses and maintaining immune tolerance. In addition to playing a role in thymic selection, DCs play an active role in tolerance under steady state conditions through several mechanisms which are dependent on IL-10, TGF-β, retinoic acid, indoleamine-2,3,-dioxygenase along with vitamin D. Several of these mechanisms are employed by DCs in induction of regulatory T cells which are comprised of Tr1 regulatory T cells, natural and inducible foxp3+ regulatory T cells, Th3 regulatory T cells and double negative regulatory T cells. It appears that certain DC subsets are highly specialized in inducing regulatory T cell differentiation and in some tissues the local microenvironment plays a role in driving DCs towards a tolerogenic response. In this review we discuss the recent advances in our understanding of the mechanisms underlying DC driven regulatory T cell induction.

Introduction

Dendritic cells (DCs) are professional antigen presenting cells and are essential mediators of immunity and tolerance. DCs are the key players in maintaining immune tolerance, for their ablation has been shown to result in autoimmunity, highlighting the active role that DCs play under steady state conditions in maintaining immune tolerance[1]. In order to prevent autoimmune reactions, self reactive lymphocytes need to be deleted or their function needs to be suppressed. The generation of normal lymphocyte repertoire which is largely self-tolerant depends on positive and negative selection, which occurs in the thymus and the process, is referred to as central tolerance. However, some self-reactive lymphocytes that escape thymic deletion enter peripheral tissues and the suppression of their function is needed to prevent autoimmune reactions, which is referred to as peripheral tolerance. Central tolerance in the thymus is largely mediated by cortical epithelial cells, medullary epithelial cells and thymic DCs and involves deletion of self reactive thymocytes along with induction of naturally occurring regulatory T cells (Tregs), which play a key role in maintaining self tolerance and suppressing a variety of pathological immune responses[2]. In contrast to central tolerance, peripheral tolerance is mediated by DCs through generation of Tregs and clonal deletion of self reactive T cells. Tregs generated in the periphery are thought to be important in controlling immune response to non-self antigens. Peripheral Tregs include IL-10 secreting Tr1 Tregs, inducible foxp3+ Tregs, Th3 cells and double negative Tregs. DC induced generation of these Treg subsets is largely mediated by IL-27, TGF-β, IL-10, retinoic acid, indoleamine-2,3-dioxygenase and vitamin D. The generation of these Tregs is either mediated by tissue resident specific DC subsets with a specialized Treg inducing function or by the action of mediators present in local tissue microenvironment, which act on DCs and drive them to behave as tolerogenic DCs and induce Treg differentiation. In this review we provide an overview of the different mechanisms employed by DCs in generation of Tregs.

Type 1 regulatory cells

Type 1 regulatory T cells (Tr1) cells are a group of Tregs characterized by production of IL-10. Although initial studies pointed towards a central role of IL-10 in mediating Tr1 generation, recent studies indicate that Tr1 generation could also be dependent on IL-27. Both IL-10 and IL-27 are produced by DCs. Aryl hydrocarbon receptor (AhR), which is a ligand-activated transcription factor belonging to the basic helix-loop-helix-PER-ARNT-SIM family, is induced in Tr1 cells and during Tr1 differentiation, physically associates with c-maf, a transcription factor belonging to the family of basic region leucine zipper domain transcription factors and activates IL-10 and IL-21 promoters[3, 4]. Studies to date have pointed towards a role of DC derived IL-27, IL-10, TGF-β1 along with a role of ICOSL signalling by DCs in induction of Tr1 cells. Figure 1 provides an overview of the pathways involved in DC mediated Tr1 differentiation.
Figure 1

DCs drive differentiation of Tr1 regulatory T cells. DCs secrete IL-27, IL-10 and TGF-β1, which induce AhR and c-maf in T cells. AhR and c-maf physically associate with each other and activate IL-10 and IL-21 promoters, driving Tr1 differentiation. IL-27 suppresses production of Th17 inducing cytokines such as IL-1β, IL-6 and IL-23 and drives Tr1 differentiation. IFN-γ suppresses Th17 inducing osteoprotegerin (OPG) and drives IL-27 production, thereby promoting Tr1 differentiation. Furthermore, PD-1/PDL-1 signaling and bacterial peptides along with vasoactive intestinal peptide (VIP) drive IL-10 production which also induces Tr1 differentiation. Moreover, ICOS/ICOSL signalling as well as TGF-β production by DCs has also been implicated in driving Tr1 differentiation.

IL-27 production by DCs drives Tr1 differentiation

DCs cultured with Foxp3+ Tregs secrete elevated levels of IL-10, IL-27 and TGF-β1, among which TGF- β1 and IL-27 are important for driving differentiation of Tr1 cells[5]. IL-27 suppresses production of Th17 polarizing cytokines IL-1β, IL-6 and IL-23 from DCs and acts on naive T cells to drive expression of the transcription factor c-maf, IL-21 and ICOS, which collectively drive differentiation of Tr1 cells[6, 7]. Furthermore, IL-27 production by DCs also drives IL-10 transcription in T cells by activation of STAT1 and STAT3, which are recruited to the IL-10 promoter, further promoting differentiation of Tr1 cells [8]. Recently, IFN-γ has also been identified to promote DC induced Tr1 generation. Studies have shown that IFN-γ inhibits Th17 inducing osteoprotegerin (OPG) in DCs and instead promotes IL-27, which drives induction of Tr1 cells[7, 9]. Hepatic DCs preferentially secrete IL-27 instead of IL-12 upon LPS stimulation, indicating that hepatic DCs may also act as inducers of Tr1 cells[10].

IL-10 production by DCs drives Tr1 differentiation

Differentiation of DCs from bone marrow in the presence of IL-10 leads to generation of a CD11clowCD45RBhigh DC subset with a plasmacytoid morphology and an immature phenotype[11]. These DCs secrete high amounts of IL-10 upon stimulation and drive differentiation of naive T cells into IL-10 secreting Tr1 cells. Similarly, skin derived langerhans cells have also been shown to produce IL-10 which can also contribute towards generation of Tr1 cells[12]. Similar to murine Tr1 cells, DCs secreting IL-10 also drives differentiation of human Tr1 cells, which is dependent on human leukocyte antigen (HLA)-G and (Ig like transcript) ILT4 molecules[13]. HLA-G, which is a non classical MHC I molecule, plays a central role in maintaining fetal-maternal tolerance during pregnancy and is expressed on IL-10 producing tolerogenic human DCs[14]. HLA-G binds to inhibitory immunoglobulin like transcript (ILT)-2 and ILT-4 receptors which has been shown to suppress DC maturation[15, 16]. IL-10 produced by DCs acts in a positive feedback manner, sustaining HLA-G and ILT4 expression on DCs along with an induction of HLA-G expression on T cells. ILT4 on tolerogenic DCs interacts with HLA-G on T cells and HLA-G on DCs interacts with ILT2 on T cells, which drives differentiation of T cells into IL-10 producing Tr1 cells[17]. Monocyte derived human DCs cultured in presence of 1α,25-dihydroxyvitamin D3 (VD3) show a semi-mature phenotype characterized by low levels of MHC Class II and costimulatory molecule expression along with production of IL-10 and impairment of IL-12 production, driving Tr1 differentiation. Moreover, DCs cultured with VD3 upregulate programmed death ligand -1 (PDL-1) upon activation, inhibition of which suppresses Tr1 differentiation[18]. PDL-1 signalling on DCs likely promotes IL-10 production, since triggering PDL-1 on DCs by soluble PD-1 has been shown to suppress DC maturation and promote IL-10 production[19]. Altogether, these studies indicate that VD3 treatment of DCs drives PDL-1 upregulation which acts as an inducer of IL-10 production by DCs, thereby driving Tr1 differentiation. However, it remains to be investigated whether HLA-G and ILT4/ILT2 signalling is involved in VD3 driven induction of Tr1 cells.

Repetitive stimulation of peripheral CD4+ T cells by immature allogeneic DCs can also drive Tr1 generation[20]. T cells cultured under stimulation by immature DCs selectively upregulate cytotoxic T-lymphocyte antigen 4 (CTLA4) and lose their ability to produce IFN-γ, IL-2, IL-4 and subsequently differentiate into Tr1 cells[21]. This is dependent on the ability of immature DCs to secrete IL-10, which is severely diminished as DCs undergo maturation. IL-10 production by pulmonary DCs also appears to be critical for induction of Tr1 induced tolerance. Pulmonary DCs in mice exposed to respiratory antigens undergo maturation but secrete IL-10 which drives induction of Tr1 cells. Moreover, these Tr1 cells can suppress airway responsiveness and their development is dependent on IL-10 production by DCs, since adoptive transfer of DCs from IL-10 deficient mice fail to induce Tr1 mediated tolerance[22]. In a model of food induced anaphylaxis, tolerance induction is mediated by gastrointestinal lamina propria DCs, whereby sugar modified antigens are targeted to C-type lectin receptor SIGNR-1, resulting in preferential production of IL-10 but not IL-6 or IL-12 p70 by DCs, which ends up driving differentiation of naive T cells into Tr1 cells[23].

Several strategies that can induce DC production of IL-10 and prevent maturation have been employed for generation of Tr1 cells. Neuropeptide vasoactive intestinal peptide is released during inflammatory/autoimmune conditions, which induces generation of DCs with a capacity to produce IL-10 and an inability to undergo complete maturation, thereby driving generation of Tr1 cells[24]. Exposure of DCs to cyclo-oxygenaase-2 overexpressing gliomas results in IL-10 production by DCs which also drives Tr1 response, which may be dependent on robust secretion of Prostaglandin E2 from the glioma[25]. Additionally, bacterial peptides such as filamentous hemagglutinin from Bortadella pertusis can directly affect DCs by suppressing their ability to produce IL-12 and instead inducing production of IL-10, which drives generation of Tr1 cells[26]. Individuals infected with Plasmodium vivax have elevated levels of Tr1 cells and culture of mononuclear cells from healthy individuals with Plasmodium vivax extracts can drive generation of Tr1 cells, indicating that certain peptides produced from Plasmodium vivax may affect DC function which leads to Tr1 generation[27].

ICOSL signalling by DCs drives Tr1 differentiation

In addition to IL-10 production by pulmonary DCs, ICOS-ICOSL signalling is also critical for Tr1 induction. Pulmonary DCs upregulate ICOSL upon maturation which is also critical for Tr1 induction since inhibition of ICOSL on pulmonary DCs suppresses Tr1 induction[28]. Plasmacytoid DCs also upregulate ICOS ligand upon maturation, which has been shown to drive differentiation of T cells into Tr1 cells[29].

TGF-β1 production by DCs drives Tr1 differentiation

TGF-β may also have a role in priming Tr1 differentiation, since addition of neutralizing antibodies against TGF-β to a coculture of CD4-CD8- splenic DCs and T cells drastically reduces the production of IL-10 by T cells[30]. CD4-CD8- spenic DC subsets secrete elevated levels of TGF-β upon stimulation with lipopolysaccharide (LPS) and subsequently prime differentiation of IL-10 producing Tr1 cells[30].

Other DC driven signals which drive Tr1 differentiation

Along with TGF-β, CD40 signaling also plays a role in the ability of CD4-CD8- DCs to prime Tr1 generation, since CD40 ligation abrogates the ability of CD4-CD8- DCs to prime Tr1 cells[31]. Furthermore, TLR9 stimulation via CpG DNA and TLR4 stimulation via LPS can convert these Tr1 inducing DCs into Th1 and Th1/Th17 inducing DCs respectively[23]. Mature pDCs isolated from peripheral blood of rheumatoid arthritis patients express high levels of indolamine-2,3-dioxygenase, which has also been implicated in promoting differentiation of T cells into Tr1 phenotype[32].

Foxp3+ Regulatory T cells

Foxp3+ regulatory T cells (Foxp3+ Tregs) are critical for maintaining immune tolerance and preventing autoimmune reactions[33]. Foxp3+ Tregs are identified by their expression of CD25 (IL-2 receptor) and Foxp3, a transcription factor critical for Treg differentiation[34]. Foxp3+ Treg population can be divided into the naturally occurring Foxp3+ Treg population (nTreg), generally found in the thymus and the inducible Treg population (iTreg), which is derived in the peripheral tissues from CD4+CD25- precursors upon activation in presence of TGF-β[35]. DCs are critical for Treg induction and in this section we offer an insight in the recent advances in our understanding of how DCs can drive nTreg and iTreg differentiation.

Naturally occurring Foxp3+ Tregs

Natural Foxp3+ Tregs (nTregs) comprise a distinct lineage pathway determined at the double positive (CD4+CD8+) stage of thymocyte development due in part to co-stimulatory signals initiating Foxp3 expression. nTregs develop in the thymus during thymic development upon recognition of self antigens. Although the role of DCs in thymic selection is documented, the role of DCs in generation of nTregs is highly controversial[36]. Several studies have shown that DCs are dispensable for nTreg generation, whereby antigens specifically expressed in thymic epithelial cells are sufficient to drive differentiation of nTregs [37]. Conversely, there are studies identifying contribution of thymic DCs to generation of nTregs[38]. Thymic DCs include two conventional DC subsets, which are CD8loSirpαhi/+ and CD8hiSirpαlo/-, among which CD8loSirpαhi/+ DCs have been shown to play a role in inducing nTreg generation in addition to their role in negative selection[39].

TSLP drives thymic DC mediated nTreg differentiation

Epithelial cells in Hassall's corpuscles in the thymus produce thymic stromal lymphopoetin (TSLP) which acts on thymic DCs by binding to TSLPR and IL-7R alpha complex and drives induction of CD80, CD86[38]. These DCs subsequently prime differentiation of CD4+CD8-CD25- thymocytes into nTregs, which is dependent on IL-2 and CD28 signaling [40]. Therefore, TSLP activated myeloid DCs in the thymus are likely critical for positive selection of medium to high affinity self reactive thymocytes to develop into nTregs[38]. In addition to myeloid DCs, plasmacytoid DCs (pDCs) residing in the thymus can also induce differentiation of CD69hiTCRhiCD4+CD8+ thymocytes into nTregs and this is dependent on CD40L crosstalk[41]. Thymic pDCs also express TSLP receptor along with IL-7 receptor complex and become responsive to TSLP produced by thymic epithelial cells of Hassall's corpuscles. TSLP activated pDCs can then drive differentiation of nTregs from CD4+CD8-CD25- thymocytes, which can be inhibited by Th1 and Th2 polarizing chemokines IL-12 and IL-4 respectively[42].

The role of TGF-β in driving nTreg differentiation is highly controversial. Previous studies have shown normal nTreg numbers in TGFβ-R1 deficient mice[35]. However, recently it has been shown that mice with TGFβ-R1 deletion have nTreg deficiency between postnatal day 3 and 5, but subsequently there is a surge in nTreg generation due to increased responsiveness of the cells to IL-2[43]. It remains to be investigated whether thymic DCs produce TGF-β1 which can affect nTreg generation.

Inducible Foxp3+ Regulatory T cells

Inducible Foxp3+ regulatory T cells (iTregs) are generated in the periphery by DCs and their generation appears to be dependent on IDO, retinoic acid, Vitamin D and TGF-β. iTregs cells play essential roles in immune tolerance and in the control of severe chronic allergic inflammation[44]. Furthermore, since iTregs are induced in the periphery, they also act as barriers in preventing the clearance of microorganisms and tumors, whereby both are known to generate conditions that can drive iTreg differentiation[45, 46]. Figure 2 provides an overview of the pathways involved in DC mediated iTreg differentiation.
Figure 2

DCs drive differentiation of foxp3 + inducible regulatory T cells. (iTregs). DCs secrete TGF-β, which induces foxp3 in naive T cells, driving differentiation of naive T cells into iTregs. Activation of AhR and TLR9 drives induction of IDO, which catalyzes tryptophan metabolism. Tryptophan metabolites promote iTreg generation through induction of TGF-β production and suppression of Th17 inducing cytokine, IL-6. Furthermore, uptake of apoptotic DCs by viable DCs along with exposure to haptens, glucocorticoids and UV radiation also induces TGF-β production, which drives iTreg differentiation. Other signals such as RANK/RANKL signalling by vitamin D treated keratinocytes and treatment of DCs with vasoactive intestinal peptide (VIP), hepatocyte growth factor (HGF) and prostaglandin-D2 (PGD2) also promote iTreg differentiation. Moreover, retinoic acid promotes iTreg differentiation by suppressing cytokines which are inhibitory to iTreg differentiation and targeting of antigen to DEC205 drives iTreg differentiation through a TGF-β dependent mechanism.

Indoleamine 2,3-dioxygenase in DCs drives iTreg differentiation

DC populations expressing indoleamine 2,3-dioxygenase (IDO) can play a critical role in immune tolerance by promoting iTreg induction[47]. IDO catalyzes tryptophan metabolism via the kynurenine pathway and therefore depletes the local environment of tryptophan. Tryptophan catabolism likely plays an important role in suppressing T cell proliferation by arresting T cells in G1 phase of cell cycle[48]. However, recent studies have highlighted an important role of tryptophan catabolites in mediating iTreg induction by exerting their effects directly on DCs. During HIV infection, IDO activity is critical in regulating Treg/Th17 balance with increased IDO levels produced by DCs, associated with a chronic inflammatory state in progressive HIV disease due to a breakdown of mucosal barrier[49]. Certain DC subsets such as pDCs, certain splenic DCs populations such as CD19+ DCs and nasal DCs have been identified to upregulate IDO upon stimulation[50]. Induction of IDO in DCs appears to be dependent on aryl hydrocarbon receptor (AhR), for DCs lacking Ahr fail to upregulate IDO and prime T cell response instead of tolerance induction[51]. Activation of Ahr in mice by 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD), commonly referred to as dioxin, for 10 days, results in IDO induction both in the lungs and spleen along with upregulation of Foxp3 in the spleen, which could be suppressed by inhibiting IDO[52].

DCs residing in the nasal lymph nodes play an important role in inducing tolerance to inhaled antigens. Studies have identified selective induction of IDO in non-plasmacytoid DCs in the nasal lymph nodes, which is critical for inducing tolerance, for abrogation of IDO induction results in elimination of tolerance induction towards the inhaled antigen[53]. In a murine model of experimental autoimmune encephalitis, IDO deficient mice show exacerbation of encephalitis, which can be inhibited by treatment with tryptophan metabolite 3-hydroxyanthranilate (3-HAA), generated during IDO mediated tryptophan catabolism. Treatment with 3-HAA drives TGF-β production from DCs and also suppresses IL-6 production, which ends up driving iTreg induction[54]. Kynurenine, the first metabolite of IDO driven tryptophan metabolism activates the AhR on T cells, thereby driving iTreg differentiation[55]. TLR9 ligation drives induction of IDO in pDCs which suppresses IL-6 production, suppressing conversion of naive T cells into Th17 cells and instead promoting iTreg induction[56]. IDO driven kynurenine generation also appears to be important for pDC mediated iTreg differentiation [57]. Human monocyte derived DCs, cultured under low tryptophan conditions, selectively upregulate inhibitory receptors ILT3 and ILT4 and drive iTreg induction[58].

TGF-β production by DCs drives iTreg differentiation

Skin DCs include langerhans cells (LCs) and dermal DCs, with LCs being frequently associated in maintenance of immune tolerance for acute depletion of LCs has been associated with an enhancement of dermal immune response[59]. Patients with langerhans cell histiocytosis, a condition with uncontrolled proliferation of LCs, show expansion of Foxp3+ Treg populations, indicating a role of LCs in Foxp3+ Treg expansion[60]. Exposure of UVR-exposed skin to haptens results in induction of iTregs, which is not observed upon LC depletion, supporting the role of LCs in inducing iTregs and suppressing immune reaction in the skin[61]. Mice with LC specific TGF-β depletion, show signs of autoimmune disease in the skin and fail to develop LCs, indicating a role for LC derived TGF-β in LC development and also pointing towards a role of LC in maintenance of immune tolerance[62]. TGF-β production by LCs could in fact be a potential mechanism of how LCs can prime differentiation of Tregs. In nickel allergy patients, administration of oral glucocorticoids leads to TGF-β production by LCs, which expands iTregs and results in reduction of clinical symptoms[63].

CD8α+ DCs were initially identified in the mouse spleen with a propensity to drive iTreg induction[64]. A unique CD8+ splenic DC subset, which expresses DEC205, a type I transmembrane protein with multiple C-type lectin domains, has been identified in the mouse spleen, and preferentially drives differentiation of iTregs[65]. CD8+DEC205+ DCs can drive iTreg differentiation both in vitro and in vivo in presence of low dose of the antigen without addition of any exogenous TGF-β. However, iTreg induction mediated by CD8+DEC205+ DCs is dependent on TGF-β for addition of TGF-β neutralizing antibody suppresses iTreg differentiation[65]. Furthermore, Polyinosinic:polycytidylic acid (poly I:C) induced maturation of CD8+DEC205+ DCs reduces their ability to drive iTregs, pointing towards their role in maintaining peripheral tolerance under steady state conditions. Targeting of small amounts of antigen to DCs by using antigen fused to DEC205 antibody under conditions of suboptimal DC activation has been shown to drive iTreg induction[66]. Another CD8- splenic subset, which expresses DCIR-2, a type II transmenbrane protein with a single external C-type lectin domain, drives iTreg differentiation when exogenous TGF-β is added. However, in absence of exogenous TGF-β, CD8- splenic DCs are better at stimulating nTregs rather than driving iTreg differentiation[65].

Pulmonary DCs mediate inhalational tolerance which occurs during non-inflammatory settings through CCR7 dependent migration of pulmonary DCs to the draining bronchial lymph node[67]. In the absence of inflammatory signal, pulmonary DCs acquire antigens and subsequently acquire a semi mature phenotype characterized by intermediate expression of costimulatory molecules and high levels of MHC II expression, followed by subsequent migration to bronchial lymph nodes, where tolerance is induced[68]. Additionally, local microenvironment in the lung also plays a role in driving iTregs. Pulmonary stromal cells can produce cytokines such as TGF-β which can drive differentiation of pulmonary DC into IL-10 and TGF-β producing DCs which can subsequently drive iTreg differentiation[69].

Uptake of apoptotic DCs by viable DCs suppresses DC maturation and instead induces production of TGF-β1 via the mTOR signalling pathway [7072]. TGF-β1 producing DCs subsequently interact with naive T cells and drive Foxp3 induction, thereby driving iTreg differentiation.

RANKL signalling on DCs drives iTreg differentiation

Local environment within skin could also contribute towards maintenance of tolerance by DCs. The interplay between vitamin D and RANKL-RANK signalling in the skin plays a role in inducing an environment which promotes DC induced iTreg induction. The activated metabolite of vitamin D (1,25-dihydroxyvitamin D3, VD3) exerts actions through its nuclear receptor, the VD3 receptor (VDR) [73]. VDR is expressed on immune cells such as DCs and Vitamin D treatment of DC inhibits maturation along with their ability to prime alloreactive T cell response[74]. Keratinocytes in the inflamed skin over express RANKL, which through RANKL-RANK signalling modulates the function of DCs in the epidermis to expand iTregs[75]. Application of topical vitamin D analog, calcipotriol, followed by transcutaneous immunization with a protein agent results in induction of iTregs, primarily due to induction of RANKL on keratinocytes which likely modulates DC function to drive iTreg differentiation[76]. iTreg induction upon topical application of vitamin D is absent in mice lacking vitamin D receptor, indicating vitamin D driven RANKL as the likely mechanism of how vitamin D can mediate skin tolerance by inducing iTregs [76].

Retinoic acid producing DCs drive iTreg differentiation

Oral intake of protein antigens leads to induction of oral tolerance, which is largely mediated through generation of iTregs in the mesenteric lymph nodes. DCs in the mesenteric lymph nodes express cyclooxygenase-2 (cox-2), which plays a role in iTreg induction. Suppression of cox-2 in mesenteric DCs results in induction of GATA-3 along with IL-4 in T cells and suppresses iTreg induction[77]. In addition to cox-2, mesenteric DCs express high levels of B7-H1 and B7-DC, which are B7 family costimulatory molecules and are also essential for mesenteric DC driven induction of iTregs[78]. The most well studied mechanism of how oral tolerance induces iTregs is through retinoic acid. Retinoic acid (RA) is an active metabolite of vitamin A which regulates multiple cellular processes such as cell death, proliferation and differentiation through the retinoic acid receptors (RAR, including α, β and γ subtypes) and the retinoic × receptors (RXR, also including α, β and γ subtypes). RA has been shown to suppress inflammatory responses in animal models of multiple diseases such as inflammatory bowel disease and experimental autoimmune encephomyelitis. A unique population of DCs, characterized by the expression of alpha E integrin, CD103 has been identified in the gut associated lymphoid tissue (GALT) as well as in the mesentereic lymph node with a specialized function of inducing Tregs and maintaining immune tolerance[79, 80]. CD103+ DCs selectively drive iTreg differentiation through RA and TGF-β dependent process, since addition of inhibitors of RA production or TGF-β neutralizing antibody suppresses iTreg induction[79, 80]. CD103+ DC derived RA also drives induction of α4β7 integrin and CCR9 on newly generated iTregs, which makes them home to GALT[81]. Furthermore, RA also sustains stability and function of iTregs, even under inflammatory setting which further results in tolerance induction[82]. The mechanism of how RA can drive iTreg induction is not completely understood. Initially, RA was thought to inhibit effects of IL-6 signaling, which promoted iTreg induction rather than induction of Th17 in presence of TGF-β[83]. Later studies indicated that RA suppresses the generation of CD44hi effector memory T cells, which secrete IL-4, IL-21 and IFN-γ, and suppress TGF-β mediated iTreg differentiation[84]. However, RA can also interfere with the effects of inhibitory cytokines on iTreg differentiation and can promote iTreg induction in absence of inhibitory cytokines, which is dependent on RAR-α[85]. Immune deficient mice lacking CD103 fail to suppress T cell mediated colitis upon transfer of Tregs, pointing towards a role of CD103+ DCs in maintaining intestinal immune homoestasis [86]. Curcumin treatment of bone marrow derived DCs drives expression of Aldh1a, an enzyme involved in RA production, which makes DCs behave similarly to mucosal CD103+ DCs and drive RA mediated induction of iTregs[87]. The local intestinal environment also modulates DC function. Intestinal epithelial cells produce TGF-β, retinoic acid which drive a tolerogenic DC phenotype, which can then subsequently drive iTreg differentiation[88, 89]. Additionally, lamina propria macrophages also suppress intestinal DC induced Th17 response, which could inadvertently prime iTreg differentiation[90].

CD103-CD11b+ DC subset has been identified in the skin and expresses 3 aldehyde dehydrogenases, which catalyze conversion of retinal to RA, giving this subset the unique property of priming iTreg differentiation[91]. Furthermore, treatment of mice with AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) has been shown to result in generation of tolerogenic DCs which promote iTreg differentiation through a RA dependent mechanism[92].

Other DC derived signals which drive iTreg differentiation

Mast cell derived Prostaglandin-D2 (PGD2) is a mediator of inflammation which promotes infiltration of eosinophils and Th2 cells into the lung during asthma. PGD2 can act through DP1 or DP2 receptor. Studies have shown that treatment of asthmatic mice with DP1 agonist can in fact suppress features of asthma by acting on pulmonary DCs and inducing cAMP dependent protein kinase A activation, which suppresses the ability of DCs to drive Th2 response and instead promotes induction of iTregs[93].

Additionally, treatment of DCs with immunosuppressive peptides has also been shown to drive iTreg differentiation. DCs treated with immunosuppressive neuropeptide, vasoactive intestinal peptide (VIP) drive iTreg differentiation, which is likely mediated by the ability of VIP to suppress DC maturation and proinflammatory cytokine production[94, 95]. Moreover, DCs upon treatment with hepatocyte growth factor (HGF) also drive iTreg differentiation, which is abrogated if DCs are treated with antibodies against HGF receptor[96]. However, the mechanisms of how HGF receptor signalling in DC drives iTreg differentiation is not understood.

Th3 cells

Th3 cells were first identified as a novel population of T cells induced upon induction of peripheral tolerance upon oral delivery of myelin basic protein, which suppressed experimental autoimmune encephalitis in mice[97]. These Th3 cells are class II-restricted T cells with identical αβ TCR as Th1 and Th2 cells. Moreover, they are characterized by production of high levels of TGF-β along with low amounts of IL-4 and IL-10 with no production of IFN-γ or IL-2. The ability of these cells to suppresses EAE is largely TGF-β dependent. Secretion of TGF-β by Th3 cells drives induction of Foxp3 in activated T cells, driving them towards iTreg phenotype[98]. Furthermore, Foxp3 can also be induced in Th3 cells for studies have shown that transient induction of TGF-β1 in T cells during activation in absence of IL-2 can drive generation of Foxp3+ Th3 cells which comprise a distinct Treg phenotype, which is CD25- and can control hyperproliferative T cell response[99].

Double negative regulatory T cells

TCR+CD3+CD4-CD8- double negative (DN) regulatory T cells inhibit immune response by Fas/FasL destruction of effector cells in an antigen specific fashion[100]. Although, the mechanisms of how DCs can prime differentiation of DN Tregs is not understood, syngeneic DCs have been successfully utilized for expansion of antigen specific DN Tregs[101].

Conclusion

DCs play a critical role in the induction of tolerance. One of the active mechanisms whereby DCs induce/maintain tolerance is through induction of Tregs. Over the last decade, significant progress has been made in understanding the DC specific signals that can drive induction of Tregs. These findings can potentially be employed to generate tolerogenic DCs which can be used for tolerance induction in hypersensitivity, autoimmunity as well as transplantation.

List of abbreviations

AhR: 

Aryl hydrocarbon receptor

cAMP: 

Cyclic adenosine monophosphate

CCR7: 

Chemokine (C-C motif) receptor 7

CTLA4: 

Cytotoxic T-lymphocyte antigen 4

Cox-2: 

Cyclooxygenase-2

DCs: 

Dendritic cells

DN: 

Double negative

GALT: 

Gut associated lymphoid tissue

HAA: 

3-hydroxyanthranilate

HGF: 

Hepatocyte growth factor

HIV: 

Human immunodeficiency virus

HLA: 

Human leukocyte antigen

ICOS: 

Inducible T cell costimulator

ICOSL: 

Inducible T cell costimulator ligand

IDO: 

Indoleamine 2,3-dioxygenase

IFN: 

Interferon

IL: 

Interleukin

ILT: 

Ig like transcript

iTreg: 

Inducible Foxp3+ regulatory T cells

LCs: 

Langerhans cells

LPS: 

Lipopolysaccharide

MHC: 

Major histocompatibility complex

mTOR: 

Mammalian target of Rapamycin

nTreg: 

Naturally occurring Foxp3+ regulatory T cells

OPG: 

Osteoprotegerin

pDC: 

Plasmacytoid dendritic cells

PDL-1: 

Programmed death ligand - 1

PGD2: 

Prostaglandin D2

Poly I: 

C: Polyinosinic:polycytidylic acid

RA: 

Retinoic acid

RANK: 

Receptor activator of nuclear factor κB

RANKL: 

Receptor activator of nuclear factor κB ligand

RAR: 

Retinoic acid receptors

RXR: 

Retinoic × receptors

STAT: 

Signal transducer and activator

TCDD: 

2,3,7,8-Tetrachlorodibenzo-p-dioxin

TGF: 

Tumor Growth Factor

TLR: 

Toll like receptor

Tr1: 

Type 1 regulatory T cells

Tregs: 

Regulatory T cells

TSLP: 

Thymic stromal lymphopoetin

UVR: 

Ultraviolet radiation

VD3: 

1α,25-dihydroxyvitamin D3

VDR: 

1α,25-dihydroxyvitamin D3 receptor

VIP: 

Vasoactive intestinal peptide.

Declarations

Acknowledgements

This work was supported in part by Operating Grants from the Canadian Institutes of Health Research, the Canadian Cystic Fibrosis Foundation, and the Foundation Fighting Blindness-Canada to J.H. J.H. was a CCFF Scholar and recipient of the CCFF Zellers Senior Scientist Award, and held a Premier's Research Excellence Award of Ontario, Canada. R.K. is a recipient of CCFF doctoral award.

Authors’ Affiliations

(1)
Physiology and Experimental Medicine Research Program, Hospital for Sick Children
(2)
Department of Laboratory Medicine and Pathobiology, University of Toronto

References

  1. Ohnmacht C, Pullner A, King SB, Drexler I, Meier S, Brocker T, Voehringer D: Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med. 2009, 206: 549-559. 10.1084/jem.20082394PubMed CentralPubMedGoogle Scholar
  2. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T: Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006, 212: 8-27. 10.1111/j.0105-2896.2006.00427.xPubMedGoogle Scholar
  3. Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, Burns EJ, Sherr DH, Weiner HL, Kuchroo VK: The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol. 2010, 11: 854-861. 10.1038/ni.1912PubMed CentralPubMedGoogle Scholar
  4. Marshall NB, Kerkvliet NI: Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells. Ann N Y Acad Sci. 2010, 1183: 25-37. 10.1111/j.1749-6632.2009.05125.xPubMed CentralPubMedGoogle Scholar
  5. Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL: A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007, 8: 1380-1389. 10.1038/ni1541PubMedGoogle Scholar
  6. Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL: IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol. 2009, 183: 2435-2443. 10.4049/jimmunol.0900568PubMed CentralPubMedGoogle Scholar
  7. Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, Sharpe AH, Karp CL, Miaw SC, Ho IC, Kuchroo VK: Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 2009, 183: 797-801. 10.4049/jimmunol.0901233PubMed CentralPubMedGoogle Scholar
  8. Iyer SS, Ghaffari AA, Cheng G: Lipopolysaccharide-Mediated IL-10 Transcriptional Regulation Requires Sequential Induction of Type I IFNs and IL-27 in Macrophages. J Immunol. 2010, 185: 6599-6607. 10.4049/jimmunol.1002041PubMed CentralPubMedGoogle Scholar
  9. Murugaiyan G, Mittal A, Weiner HL: Identification of an IL-27/osteopontin axis in dendritic cells and its modulation by IFN-gamma limits IL-17-mediated autoimmune inflammation. Proc Natl Acad Sci USA. 2010, 107: 11495-11500. 10.1073/pnas.1002099107PubMed CentralPubMedGoogle Scholar
  10. Chen Y, Jiang G, Yang HR, Gu X, Wang L, Hsieh CC, Chou HS, Fung JJ, Qian S, Lu L: Distinct response of liver myeloid dendritic cells to endotoxin is mediated by IL-27. J Hepatol. 2009, 51: 510-519. 10.1016/j.jhep.2009.04.026PubMed CentralPubMedGoogle Scholar
  11. Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F, Groux H: Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity. 2003, 18: 605-617. 10.1016/S1074-7613(03)00113-4PubMedGoogle Scholar
  12. Igyarto BZ, Jenison MC, Dudda JC, Roers A, Muller W, Koni PA, Campbell DJ, Shlomchik MJ, Kaplan DH: Langerhans cells suppress contact hypersensitivity responses via cognate CD4 interaction and langerhans cell-derived IL-10. J Immunol. 2009, 183: 5085-5093. 10.4049/jimmunol.0901884PubMed CentralPubMedGoogle Scholar
  13. Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, Hauben E, Roncarolo MG: Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood. 2010, 116: 935-944. 10.1182/blood-2009-07-234872PubMedGoogle Scholar
  14. Hunt JS, Petroff MG, McIntire RH, Ober C: HLA-G and immune tolerance in pregnancy. Faseb J. 2005, 19: 681-693. 10.1096/fj.04-2078revPubMedGoogle Scholar
  15. Allan DS, Lepin EJ, Braud VM, O'Callaghan CA, McMichael AJ: Tetrameric complexes of HLA-E, HLA-F, and HLA-G. J Immunol Methods. 2002, 268: 43-50. 10.1016/S0022-1759(02)00199-0PubMedGoogle Scholar
  16. Ristich V, Liang S, Zhang W, Wu J, Horuzsko A: Tolerization of dendritic cells by HLA-G. Eur J Immunol. 2005, 35: 1133-1142. 10.1002/eji.200425741PubMedGoogle Scholar
  17. Gregori S, Magnani CF, Roncarolo MG: Role of human leukocyte antigen-G in the induction of adaptive type 1 regulatory T cells. Hum Immunol. 2009, 70: 966-969. 10.1016/j.humimm.2009.07.022PubMedGoogle Scholar
  18. Unger WW, Laban S, Kleijwegt FS, van der Slik AR, Roep BO: Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. Eur J Immunol. 2009, 39: 3147-3159. 10.1002/eji.200839103PubMedGoogle Scholar
  19. Kuipers H, Muskens F, Willart M, Hijdra D, van Assema FB, Coyle AJ, Hoogsteden HC, Lambrecht BN: Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol. 2006, 36: 2472-2482. 10.1002/eji.200635978PubMedGoogle Scholar
  20. Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG: Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood. 2005, 105: 1162-1169.PubMedGoogle Scholar
  21. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH: Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med. 2000, 192: 1213-1222. 10.1084/jem.192.9.1213PubMed CentralPubMedGoogle Scholar
  22. Akbari O, DeKruyff RH, Umetsu DT: Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol. 2001, 2: 725-731. 10.1038/90667PubMedGoogle Scholar
  23. Zhou Y, Kawasaki H, Hsu SC, Lee RT, Yao X, Plunkett B, Fu J, Yang K, Lee YC, Huang SK: Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1. Nat Med. 2010, 16: 1128-1133. 10.1038/nm.2201PubMed CentralPubMedGoogle Scholar
  24. Gonzalez-Rey E, Chorny A, Fernandez-Martin A, Ganea D, Delgado M: Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. Blood. 2006, 107: 3632-3638. 10.1182/blood-2005-11-4497PubMed CentralPubMedGoogle Scholar
  25. Akasaki Y, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS: Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol. 2004, 173: 4352-4359.PubMedGoogle Scholar
  26. McGuirk P, McCann C, Mills KH: Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med. 2002, 195: 221-231. 10.1084/jem.20011288PubMed CentralPubMedGoogle Scholar
  27. Jangpatarapongsa K, Chootong P, Sattabongkot J, Chotivanich K, Sirichaisinthop J, Tungpradabkul S, Hisaeda H, Troye-Blomberg M, Cui L, Udomsangpetch R: Plasmodium vivax parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells. Eur J Immunol. 2008, 38: 2697-2705. 10.1002/eji.200838186PubMed CentralPubMedGoogle Scholar
  28. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT: Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med. 2002, 8: 1024-1032. 10.1038/nm745PubMedGoogle Scholar
  29. Ito T, Yang M, Wang YH, Lande R, Gregorio J, Perng OA, Qin XF, Liu YJ, Gilliet M: Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J Exp Med. 2007, 204: 105-115. 10.1084/jem.20061660PubMed CentralPubMedGoogle Scholar
  30. Zhang X, Huang H, Yuan J, Sun D, Hou WS, Gordon J, Xiang J: CD4-8- dendritic cells prime CD4+ T regulatory 1 cells to suppress antitumor immunity. J Immunol. 2005, 175: 2931-2937.PubMedGoogle Scholar
  31. Zhang X, Kedl RM, Xiang J: CD40 ligation converts TGF-beta-secreting tolerogenic CD4-8- dendritic cells into IL-12-secreting immunogenic ones. Biochem Biophys Res Commun. 2009, 379: 954-958. 10.1016/j.bbrc.2008.12.179PubMedGoogle Scholar
  32. Kavousanaki M, Makrigiannakis A, Boumpas D, Verginis P: Novel role of plasmacytoid dendritic cells in humans: induction of interleukin-10-producing Treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy. Arthritis Rheum. 2010, 62: 53-63. 10.1002/art.25037PubMedGoogle Scholar
  33. Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell. 2008, 133: 775-787. 10.1016/j.cell.2008.05.009PubMedGoogle Scholar
  34. Zheng Y, Rudensky AY: Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 2007, 8: 457-462. 10.1038/ni1455PubMedGoogle Scholar
  35. Curotto de Lafaille MA, Lafaille JJ: Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity. 2009, 30: 626-635. 10.1016/j.immuni.2009.05.002PubMedGoogle Scholar
  36. Wirnsberger G, Hinterberger M, Klein L: Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol Cell Biol. 2011, 89: 45-53. 10.1038/icb.2010.123PubMedGoogle Scholar
  37. Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L: Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007, 8: 351-358. 10.1038/ni1444PubMedGoogle Scholar
  38. Ziegler SF, Liu YJ: Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol. 2006, 7: 709-714.PubMedGoogle Scholar
  39. Proietto AI, van Dommelen S, Zhou P, Rizzitelli A, D'Amico A, Steptoe RJ, Naik SH, Lahoud MH, Liu Y, Zheng P: Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc Natl Acad Sci USA. 2008, 105: 19869-19874. 10.1073/pnas.0810268105PubMed CentralPubMedGoogle Scholar
  40. Watanabe N, Wang YH, Lee HK, Ito T, Cao W, Liu YJ: Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature. 2005, 436: 1181-1185. 10.1038/nature03886PubMedGoogle Scholar
  41. Martin-Gayo E, Sierra-Filardi E, Corbi AL, Toribio ML: Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development. Blood. 2010, 115: 5366-5375. 10.1182/blood-2009-10-248260PubMedGoogle Scholar
  42. Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, Arima K, Wang YH, Voo KS, Cao W, Liu YJ: Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol. 2010, 184: 2999-3007. 10.4049/jimmunol.0804106PubMed CentralPubMedGoogle Scholar
  43. Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W: A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol. 2008, 9: 632-640.PubMedGoogle Scholar
  44. Curotto de Lafaille MA, Kutchukhidze N, Shen S, Ding Y, Yee H, Lafaille JJ: Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity. 2008, 29: 114-126. 10.1016/j.immuni.2008.05.010PubMedGoogle Scholar
  45. Curiel TJ: Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008, 20: 241-246. 10.1016/j.coi.2008.04.008PubMed CentralPubMedGoogle Scholar
  46. Wohlfert E, Belkaid Y: Role of endogenous and induced regulatory T cells during infections. J Clin Immunol. 2008, 28: 707-715. 10.1007/s10875-008-9248-6PubMed CentralPubMedGoogle Scholar
  47. Munn DH, Mellor AL: Indoleamine 2, 3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007, 117: 1147-1154. 10.1172/JCI31178PubMed CentralPubMedGoogle Scholar
  48. Brandacher G, Margreiter R, Fuchs D: Clinical relevance of indoleamine 2, 3-dioxygenase for alloimmunity and transplantation. Curr Opin Organ Transplant. 2008, 13: 10-15. 10.1097/MOT.0b013e3282f3df26PubMedGoogle Scholar
  49. Favre D, Mold J, Hunt PW, Kanwar B, Loke P, Seu L, Barbour JD, Lowe MM, Jayawardene A, Aweeka F: Tryptophan catabolism by indoleamine 2, 3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med. 2010, 2: 32ra36.PubMed CentralPubMedGoogle Scholar
  50. Mellor AL, Baban B, Chandler PR, Manlapat A, Kahler DJ, Munn DH: Cutting edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2, 3-dioxygenase-dependent T cell regulatory functions via IFN Type 1 signaling. J Immunol. 2005, 175: 5601-5605.PubMedGoogle Scholar
  51. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T: Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA. 2010, 107: 19961-19966. 10.1073/pnas.1014465107PubMed CentralPubMedGoogle Scholar
  52. Vogel CF, Goth SR, Dong B, Pessah IN, Matsumura F: Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2, 3-dioxygenase. Biochem Biophys Res Commun. 2008, 375: 331-335. 10.1016/j.bbrc.2008.07.156PubMed CentralPubMedGoogle Scholar
  53. van der Marel AP, Samsom JN, Greuter M, van Berkel LA, O'Toole T, Kraal G, Mebius RE: Blockade of IDO inhibits nasal tolerance induction. J Immunol. 2007, 179: 894-900.PubMedGoogle Scholar
  54. Yan Y, Zhang GX, Gran B, Fallarino F, Yu S, Li H, Cullimore ML, Rostami A, Xu H: IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol. 2010, 185: 5953-5961. 10.4049/jimmunol.1001628PubMed CentralPubMedGoogle Scholar
  55. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA: An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010, 185: 3190-3198. 10.4049/jimmunol.0903670PubMed CentralPubMedGoogle Scholar
  56. Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL: IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol. 2009, 183: 2475-2483. 10.4049/jimmunol.0900986PubMed CentralPubMedGoogle Scholar
  57. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR: The indoleamine 2, 3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008, 181: 5396-5404.PubMed CentralPubMedGoogle Scholar
  58. Brenk M, Scheler M, Koch S, Neumann J, Takikawa O, Hacker G, Bieber T, von Bubnoff D: Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J Immunol. 2009, 183: 145-154. 10.4049/jimmunol.0803277PubMedGoogle Scholar
  59. Bobr A, Olvera-Gomez I, Igyarto BZ, Haley KM, Hogquist KA, Kaplan DH: Acute ablation of Langerhans cells enhances skin immune responses. J Immunol. 2010, 185: 4724-4728. 10.4049/jimmunol.1001802PubMed CentralPubMedGoogle Scholar
  60. Senechal B, Elain G, Jeziorski E, Grondin V, Patey-Mariaud de Serre N, Jaubert F, Beldjord K, Lellouch A, Glorion C, Zerah M: Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med. 2007, 4: e253. 10.1371/journal.pmed.0040253PubMed CentralPubMedGoogle Scholar
  61. Schwarz A, Noordegraaf M, Maeda A, Torii K, Clausen BE, Schwarz T: Langerhans cells are required for UVR-induced immunosuppression. J Invest Dermatol. 2010, 130: 1419-1427. 10.1038/jid.2009.429PubMedGoogle Scholar
  62. Kaplan DH, Li MO, Jenison MC, Shlomchik WD, Flavell RA, Shlomchik MJ: Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells. J Exp Med. 2007, 204: 2545-2552. 10.1084/jem.20071401PubMed CentralPubMedGoogle Scholar
  63. Stary G, Klein I, Bauer W, Koszik F, Reininger B, Kohlhofer S, Gruber K, Skvara H, Jung T, Stingl G: Glucocorticosteroids modify Langerhans cells to produce TGF-beta and expand regulatory T cells. J Immunol. 2010, 186: 103-112.PubMedGoogle Scholar
  64. Stock P, Akbari O, Berry G, Freeman GJ, Dekruyff RH, Umetsu DT: Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol. 2004, 5: 1149-1156. 10.1038/ni1122PubMedGoogle Scholar
  65. Yamazaki S, Dudziak D, Heidkamp GF, Fiorese C, Bonito AJ, Inaba K, Nussenzweig MC, Steinman RM: CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells. J Immunol. 2008, 181: 6923-6933.PubMed CentralPubMedGoogle Scholar
  66. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H: Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005, 6: 1219-1227. 10.1038/ni1265PubMedGoogle Scholar
  67. Hintzen G, Ohl L, del Rio ML, Rodriguez-Barbosa JI, Pabst O, Kocks JR, Krege J, Hardtke S, Forster R: Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node. J Immunol. 2006, 177: 7346-7354.PubMedGoogle Scholar
  68. Lambrecht BN, Hammad H: Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat Rev Immunol. 2003, 3: 994-1003. 10.1038/nri1249PubMedGoogle Scholar
  69. Li Q, Guo Z, Xu X, Xia S, Cao X: Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammation. Eur J Immunol. 2008, 38: 2751-2761. 10.1002/eji.200838542PubMedGoogle Scholar
  70. Kushwah R, Wu J, Oliver JR, Jiang G, Zhang J, Siminovitch KA, Hu J: Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg. Eur J Immunol. 2010, 40: 1022-1035. 10.1002/eji.200939782PubMed CentralPubMedGoogle Scholar
  71. Kushwah R, Oliver JR, Zhang J, Siminovitch KA, Hu J: Apoptotic dendritic cells induce tolerance in mice through suppression of dendritic cell maturation and induction of antigen-specific regulatory T cells. J Immunol. 2009, 183: 7104-7118. 10.4049/jimmunol.0900824PubMed CentralPubMedGoogle Scholar
  72. Kushwah R, Hu J: Dendritic cell apoptosis: regulation of tolerance versus immunity. J Immunol. 2010, 185: 795-802. 10.4049/jimmunol.1000325PubMedGoogle Scholar
  73. Carlberg C, Bendik I, Wyss A, Meier E, Sturzenbecker LJ, Grippo JF, Hunziker W: Two nuclear signalling pathways for vitamin D. Nature. 1993, 361: 657-660. 10.1038/361657a0PubMedGoogle Scholar
  74. Penna G, Adorini L: 1 Alpha, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000, 164: 2405-2411.PubMedGoogle Scholar
  75. Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S, Schwarz T, Penninger JM, Beissert S: Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006, 12: 1372-1379.PubMedGoogle Scholar
  76. Ghoreishi M, Bach P, Obst J, Komba M, Fleet JC, Dutz JP: Expansion of antigen-specific regulatory T cells with the topical vitamin d analog calcipotriol. J Immunol. 2009, 182: 6071-6078. 10.4049/jimmunol.0804064PubMed CentralPubMedGoogle Scholar
  77. Broere F, du Pre MF, van Berkel LA, Garssen J, Schmidt-Weber CB, Lambrecht BN, Hendriks RW, Nieuwenhuis EE, Kraal G, Samsom JN: Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4. Mucosal Immunol. 2009, 2: 254-264. 10.1038/mi.2009.2PubMedGoogle Scholar
  78. Fukaya T, Takagi H, Sato Y, Sato K, Eizumi K, Taya H, Shin T, Chen L, Dong C, Azuma M: Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3+ regulatory T cells in the establishment of oral tolerance. Blood. 2010, 116: 2266-2276. 10.1182/blood-2009-10-250472PubMed CentralPubMedGoogle Scholar
  79. Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y: Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007, 204: 1775-1785. 10.1084/jem.20070602PubMed CentralPubMedGoogle Scholar
  80. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F: A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007, 204: 1757-1764. 10.1084/jem.20070590PubMed CentralPubMedGoogle Scholar
  81. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ: All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007, 204: 1765-1774. 10.1084/jem.20070719PubMed CentralPubMedGoogle Scholar
  82. Zhou X, Kong N, Wang J, Fan H, Zou H, Horwitz D, Brand D, Liu Z, Zheng SG: Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J Immunol. 2010, 185: 2675-2679. 10.4049/jimmunol.1000598PubMed CentralPubMedGoogle Scholar
  83. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H: Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007, 317: 256-260. 10.1126/science.1145697PubMedGoogle Scholar
  84. Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P, Belkaid Y, Mathis D, Benoist C: Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity. 2008, 29: 758-770. 10.1016/j.immuni.2008.09.018PubMed CentralPubMedGoogle Scholar
  85. Nolting J, Daniel C, Reuter S, Stuelten C, Li P, Sucov H, Kim BG, Letterio JJ, Kretschmer K, Kim HJ, von Boehmer H: Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J Exp Med. 2009, 206: 2131-2139. 10.1084/jem.20090639PubMed CentralPubMedGoogle Scholar
  86. Annacker O, Coombes JL, Malmstrom V, Uhlig HH, Bourne T, Johansson-Lindbom B, Agace WW, Parker CM, Powrie F: Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J Exp Med. 2005, 202: 1051-1061. 10.1084/jem.20040662PubMed CentralPubMedGoogle Scholar
  87. Cong Y, Wang L, Konrad A, Schoeb T, Elson CO: Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cells. Eur J Immunol. 2009, 39: 3134-3146. 10.1002/eji.200939052PubMedGoogle Scholar
  88. Iliev ID, Spadoni I, Mileti E, Matteoli G, Sonzogni A, Sampietro GM, Foschi D, Caprioli F, Viale G, Rescigno M: Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells. Gut. 2009, 58: 1481-1489. 10.1136/gut.2008.175166PubMedGoogle Scholar
  89. Iliev ID, Mileti E, Matteoli G, Chieppa M, Rescigno M: Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol. 2009, 2: 340-350. 10.1038/mi.2009.13PubMedGoogle Scholar
  90. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B: Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol. 2007, 8: 1086-1094. 10.1038/ni1511PubMedGoogle Scholar
  91. Guilliams M, Crozat K, Henri S, Tamoutounour S, Grenot P, Devilard E, de Bovis B, Alexopoulou L, Dalod M, Malissen B: Skin-draining lymph nodes contain dermis-derived CD103(-) dendritic cells that constitutively produce retinoic acid and induce Foxp3(+) regulatory T cells. Blood. 2010, 115: 1958-1968. 10.1182/blood-2009-09-245274PubMedGoogle Scholar
  92. Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM, Burns EJ, Weiner HL: An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2010, 107: 20768-20773. 10.1073/pnas.1009201107PubMed CentralPubMedGoogle Scholar
  93. Hammad H, Kool M, Soullie T, Narumiya S, Trottein F, Hoogsteden HC, Lambrecht BN: Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells. J Exp Med. 2007, 204: 357-367. 10.1084/jem.20061196PubMed CentralPubMedGoogle Scholar
  94. Chorny A, Gonzalez-Rey E, Delgado M: Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation. Ann N Y Acad Sci. 2006, 1088: 187-194. 10.1196/annals.1366.004PubMedGoogle Scholar
  95. Chorny A, Gonzalez-Rey E, Ganea D, Delgado M: Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo: therapeutic applications in autoimmunity and transplantation. Ann N Y Acad Sci. 2006, 1070: 190-195. 10.1196/annals.1317.011PubMedGoogle Scholar
  96. Benkhoucha M, Santiago-Raber ML, Schneiter G, Chofflon M, Funakoshi H, Nakamura T, Lalive PH: Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc Natl Acad Sci USA. 2010, 107: 6424-6429. 10.1073/pnas.0912437107PubMed CentralPubMedGoogle Scholar
  97. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994, 265: 1237-1240. 10.1126/science.7520605PubMedGoogle Scholar
  98. Carrier Y, Yuan J, Kuchroo VK, Weiner HL: Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol. 2007, 178: 179-185.PubMedGoogle Scholar
  99. Carrier Y, Yuan J, Kuchroo VK, Weiner HL: Th3 cells in peripheral tolerance. II. TGF-beta-transgenic Th3 cells rescue IL-2-deficient mice from autoimmunity. J Immunol. 2007, 178: 172-178.PubMedGoogle Scholar
  100. Zhang ZX, Yang L, Young KJ, DuTemple B, Zhang L: Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med. 2000, 6: 782-789. 10.1038/77513PubMedGoogle Scholar
  101. Thomson CW, Mossoba ME, Siatskas C, Chen W, Sung A, Medin JA, Zhang L: Lentivirally transduced recipient-derived dendritic cells serve to ex vivo expand functional FcRgamma-sufficient double-negative regulatory T cells. Mol Ther. 2007, 15: 818-824.PubMedGoogle Scholar

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© Kushwah and Hu; licensee BioMed Central Ltd. 2011

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