Immunology

Volume 132, Issue 3 p. 307-314

Free Access

Tolerogenic dendritic cells and their potential applications

Jim Hu,

Jim Hu

Physiology and Experimental Medicine Research Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON

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Yonghong Wan,

Yonghong Wan

Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, ON, Canada

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Jim Hu,

Jim Hu

Physiology and Experimental Medicine Research Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON

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Yonghong Wan,

Yonghong Wan

Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, ON, Canada

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First published: 05 January 2011

https://doi.org/10.1111/j.1365-2567.2010.03396.x

Citations: 55

Dr J. Hu, Physiology and Experimental Medicine Research Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8. Email: [email protected]
Senior author: Jim Hu

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Summary

Dendritic cells (DCs) play a pivotal role in regulating the balance between immunity and tolerance of the immune system. Recent advancements in DC biology and techniques for manipulating the function of these cells have shown their immense therapeutic potential for treating a variety of immune disorders. Theoretically, antigen-specific tolerogenic DCs can be generated in vitro and delivered to patients to correct the dysfunctional immune responses that attack their own tissues or over-react to innocuous foreign antigens. However, DCs are a heterogeneous population of cells with differences in cell surface makers, differentiation pathways and functions. Studies are needed to examine which subset of DCs can be used for what type of applications. Furthermore, most of the information on tolerogenic DCs has been obtained from animal models and translational studies are needed to examine how a DC therapeutic strategy can be implemented clinically to modulate immunity.

Introduction

Dendritic cells (DCs) are a heterogeneous group of cells that are specialized in the regulation of immune responses. Although DCs were discovered by Steinman in his pursuit to understand immunogenicity,¹ these cells play an equally important role in maintaining immune tolerance.² Despite being discovered relatively late compared with other immune cells, such as T cells and B cells, the importance of DCs in regulating the immune system led to an intensive quest for knowledge on these cells over the past few decades. As a result, a huge body of information was generated regarding their development, functions and cell surface marker expression. Several recent articles provide detailed information on DC development and function.^3–5 In this review, we will focus on the role of DCs in peripheral tolerance and potential applications of tolerogenic DCs. Most studies in this area were conducted with mouse models, so this review will discuss mainly work carried out with mouse DCs.

Bone-marrow-derived murine DCs can be classified into three subpopulations based on their lineages during development, classic DCs (cDCs), plasmacytoid DCs (pDCs) and tumour necrosis factor and inducible oxide synthase-producing DCs (TipDCs). All these subpopulations originated from a common myeloid progenitor cell called monocyte, macrophage and DC precursor.^4,5 The monocyte, macrophage and DC precursor can be differentiated into common DC precursors in the presence of fms-like tyrosine kinase 3 ligand (Flt3L) or monocytes in the presence of macrophage colony-stimulating factor. In bone marrow, common DC precursors give rise to pDCs or pre-cDCs that travel through blood to peripheral destinations to differentiate into cDCs. Under inflammatory conditions, monocytes can differentiate into TipDCs. Based on cell surface markers and anatomic locations, cDCs can be further divided into subsets. For example, in lymphoid tissues such as the mouse spleen, two subsets of cDCs, CD8⁺ CD205⁺ and CD8⁻ 33D1⁺, are localized in different cell zones.⁶ In non-lymphoid tissues, such as lung and liver, there are also two subsets of cDCs,⁷ CD103⁺ CD11b⁺ and CD103⁻ CD11b^hi. Unlike the cDCs, pDCs are relatively long-lived DCs and they produce type I interferon in response to viral infection.^8,9 The monocyte-derived TipDCs also play an important role in enhancing host immune responses to infections through the secretion of tumour necrosis factor-α and nitric oxide, reminiscent of activated macrophages.^10–13

Langerhans cells in the skin epidermis are functionally related to DCs and have been considered as another DC subpopulation.^14–18 Accumulating evidence suggests that Langerhans cells originate from an embryonic precursor that migrates into the epidermis during late embryonic development.¹⁹ Langerhans cells can renew themselves locally, independent of adult circulating precursors, under steady-state conditions, whereas under severe inflammatory conditions, they can be repopulated by circulating blood precursors.²⁰

DC functions

Generation of antigen-specific immune responses

The important role of DCs in immunity was first recognized by Steinman et al. using mixed leucocyte reaction assays^21,22 and the splenic DCs were found to be the major cell type required for the induction of lymphocyte responses. The DCs are located in both lymphoid and non-lympoid tissues.^7,23,24 They take up antigenic materials from internal and external sources, such as infected host cells or infectious microorganisms, and process and present them to naive T cells. Upon interacting with DCs, naive T cells can be differentiated into helper T cells to regulate the function of other T cells or B cells, or into cytotoxic T cells to eliminate the infected cells or further into memory T cells to defend the body from future infection by the same source. For a naive T cell to differentiate, its T-cell receptor must be engaged and co-stimulatory pathways must be activated. In addition, a particular cytokine environment is also needed to programme the differentiation of a particular T-cell response. Dendritic cells express high levels of MHC class I and II molecules on the cell surface and these molecules bind processed antigens for presentation to T cells. Under certain conditions, such as inflammation, co-stimulatory molecule expression is also elevated in DCs. In addition, DCs can secrete cytokines that can influence the direction of T-cell differentiation. For instance, a naive CD4⁺ T cell can be differentiated into antigen-specific T helper type 1, type 2 or type 17 cells depending on the cytokine environment.^25,26 Although other cells, such as B cells and macrophages, can also present antigens, DCs are the most efficient professional antigen-presenting cells.

Generation of antigen-specific tolerance

Dendritic cells are important not only in the generation of T-cell immune responses, but also in immune tolerance. As antigens can be derived endogenously from the host cells or externally from foreign entities, the immune system has to be able to distinguish between innocuous and harmful antigens to avoid autoimmune diseases or undesired immune responses. Therefore, immune tolerance has to be in place to maintain homeostatic balance. The antigen-specific immune tolerance can be generated in thymus or peripheral tissues. T cells are developed in the thymus from their progenitors, which enter the thymus through blood vessels near the corticomedullary junction. Within the thymus, T cells go through positive and negative selection processes in anatomically different locations to shape the entire peripheral T-cell repertoire. New developments regarding T-cell selection and generation of immune tolerance in the thymus has recently been reviewed by Klein et al.²⁷ It is clear that in addition to thymic epithelial cells, DCs in thymus play an important role in the generation of central immune tolerance.^27,28 The central tolerance is achieved by deletion of potentially self-reactive antigen-specific T cells as well as by the generation of regulatory T (Treg) cells.²⁹ Antigen-specific Treg cells generated in the thymus are CD4⁺ CD25⁺ Foxp3⁺ and also called natural regulatory T cells or nTreg cells. These cells exert their tolerogenic effects on other T cells in a contact-dependent fashion along with secretion of anti-inflammatory cytokines such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10).³⁰

Peripheral tolerance can be generated by DCs via several mechanisms, including generation and expansion of Treg cells, T-cell deletion or induction of anergy.^31–33 CD4⁺ CD25⁺ Foxp3⁺ Treg cells can develop in the periphery under subimmunogenic antigen presentation, during chronic inflammation or during normal homeostasis of the gut.³⁴ These induced regulatory T cells are also called iTreg cells. In addition, there are other types of peripheral Treg cells, such as Th3 (CD4⁺ TGF-β⁺Foxp3⁺) and Tr1 (CD4⁺ IL-10⁺ Foxp3⁻).³⁵ Dendritic cells are shown to be essential for the development of these Treg cells both in vitro and in vivo.³⁶ In addition to the generation of Treg cells, presentation of antigens from dying cells by DCs³⁷ or low doses of intact soluble proteins targeted to DCs in the steady state,² can lead to antigen-specific tolerance through deletion of corresponding T cells. Finally, T-cell anergy (partial or total unresponsiveness) is an important part of peripheral tolerance^38,39 and DCs are required for generation of T-cell anergy.

Modulation of functions of other cells

In addition to the antigen-specific activation of T cells for the development of immunity and tolerance, DCs can influence the functions of other immune cells.³ First, DCs are shown to play an important role in B-cell activation.^40,41 Although DCs are known to process internalized antigens to present degradative products on MHC for T-cell receptor recognition, they can retain antigens in their native form for the engagement of B-cell receptors on B cells. Second, DCs are involved in priming and proliferation of natural killer (NK) cells.^42,43 Natural killer cells play an important role in host defence against viral infection; IL-15 is required for NK development^44,45 and DCs are required to trans-present IL-15 on their high affinity IL-15 receptor to activate NK cells⁴² and to produce IL-15 for NK proliferation.⁴³ Third, DCs are required for myeloid homeostasis; depletion of murine DCs in mice leads to systemic myeloid expansion.³ The elevation of the serum levels of Flt3L because of the lack of DCs is probably responsible for the myeloid expansion. Finally, DCs are required for implantation during embryonic development.⁴⁶ It has been shown in a transgenic mouse model allowing conditional ablation of uterine DCs in a spatially and temporally regulated manner that depletion of uterine DCs resulted in a severe impairment of the implantation process, leading to embryo resorption.⁴⁶

In vitro generation of tolerogenic DCs

Following the establishment of protocols for the generation of DCs from murine bone marrow^47,48 or human peripheral blood,⁴⁹ the potential of DCs for clinical applications has been under intensive investigation.^2,50,51 As DCs are involved in the regulation of both immunity and tolerance, they have, conceptually, a variety of clinical applications for treatment of diseases that result from immune deficiency or imbalance. Over the past two decades, a large body of information has been accumulated regarding DC development,^3–5 maturation,^51–53 and migration,^54,55as well as in vitro manipulation.^47,48,56,57 This accumulated body of knowledge is useful for therapeutic development using antigen-loaded tolerogenic DCs.

Growth factor-engendered immature DCs

Since immature DCs play a key role in maintaining self-tolerance under steady-state conditions, considerable effort has been made over the last decade to use immature DCs generated in vitro for tolerance induction.^58,59 The most commonly used growth factors are IL-10, TGF-β, hepatocyte growth factor and vasoactive intestinal peptide.^60–62 Dendritic cells generated under these conditions typically present low numbers of self-peptide–MHC complexes (signal 1) coupled with limited co-stimulatory molecule expression (signal 2) and pro-inflammatory cytokine production (signal 3), leading to T-cell anergy and apoptosis.⁶³ Upon adoptive transfer, antigen-specific tolerance induction could be achieved in a variety of animal models. More encouragingly, Lutz and colleagues have shown that immature DCs can be generated from human bone marrow by low doses of granulocyte–macrophage colony-stimulating factor (GM-CSF) in the absence of IL-4 under good manufacturing practices conditions. Dendritic cells generated in such a way are resistant to maturation in response to Toll-like receptor agonists or CD40 ligation,⁶⁴ though their ability to retain an immature state in vivo following adoptive transfer remains elusive.

Genetically modified immature DCs

One attempt to maintain the immature phenotype following in vivo delivery is to genetically modify DCs with viral vectors that express anti-inflammatory cytokines such as IL-10, IL-4 or TGF-β.^65,66 Presumably, continued exposure to these cytokines secreted by DCs themselves will prevent them from undergoing maturation. Furthermore, these cytokines may provide additional help to facilitate the generation of regulatory T cells or deviate from the T helper type 2 response during DC–T-cell interaction.^67–70 This gene-transfer approach has also been extended to encode other transgenes such as pro-apoptotic molecules (e.g. CD95 ligand and tumour necrosis factor-related apoptosis-inducing ligand) and immunoregulatory proteins (e.g. Indoleamine 2,3-dioxygenase and cytotoxic T lymphocyte antigen 4), which directly eliminate effector T cells or suppress their functions.^71–75 In addition to viral vectors, recent development of small interference RNA technology allows silencing of pro-inflammatory cytokine, such as IL-12, to reduce DC immunogenicity.⁷⁶

Immunosuppressive drug-induced tolerogenic DCs

Immunosuppressive drugs such as corticosteroids, cyclosporine, tacrolimus, rapamycin, deoxyspergualin, vitamin D3, mycophenolate mofetil and sanglifehrin A have been used to modulate DC differentiation and function. Lee et al.⁷⁷ showed that cyclosporine A or tacrilumus could inhibit DC maturation through blocking nuclear factor-κB. This effect could be overcome, at least in part, by IL-4 but augmented by TGF-β. Generation of tolerogenic DCs by LF15-0195, a potent deoxyspergualin, appears also to be through suppression of nuclear factor-κB signalling and these DCs are refractory to tumour necrosis factor-α or lipopolysaccharide-induced maturation, retaining a stable immature state.⁷⁸

Both vitamin D3 and dexamethasone can influence DC differentiation by down-regulating their capacity for IL-12p70 secretion. The resultant DCs are able to convert CD4⁺ T cells into IL-10-secreting Treg cells, potently suppressing the proliferation of responder T cells. However, up-regulation of PD-L1 was noted only on vitamin D3-treated DCs but not dexamethasone-treated DCs and blockade of PD-L1 abolished the regulatory capacity of vitamin D3-DCs.⁷⁹ Different from other immunosuppressive drugs, rapamycin appears to have a more versatile effect on DC differentiation and function. It has been reported that rapamycin suppresses the functional activation of bone-marrow-derived DCs that can induce the production of CD4⁺ CD25⁺ foxp3⁺ Treg cells, both in vitro and in vivo, and promote organ transplant tolerance.^80–82 Others reported that inhibition of mammalian target of rapamycin (mTOR) during differentiation did not affect the acquisition of a DC phenotype but instead promoted apoptosis of monocyte- or CD34-derived DCs.^83,84 However, a recent study showed that rapamycin increased pro-inflammatory cytokines produced by Toll-like receptor-activated myeloid DCs, blocked their IL-10 production and signal transducer and activator of transcription 3 activity, and significantly increased the T-cell allostimulatory potential of myeloid DCs.⁸⁵ Similarly, rapamycin has been linked to enhanced antigen presentation through induction of autophagy in DCs.⁸⁶ Collectively, mTOR exerts divergent immunoregulatory functions during DC activation and differentiation depending on the DC type, and the dose and duration of rapamycin exposure.

Potential applications of tolerogenic DCs

In addition to in vitro manipulation of DC phenotype and functions, strategies to target immature DCs in vivo have also been investigated. For instance, targeting of DEC-205-expressing CD8α⁺ DC with an anti-DEC-205 antibody–peptide fusion molecule results in efficient deletion of the corresponding peptide-specific T cells, and induction of FoxP3-expressing Treg cells.^87,88 An additional example is the tolerogenic influence of apoptotic cells on immature DCs.^89–93 Together, these in vitro and in vivo approaches offer potential applications of tolerogenic DCs in autoimmunity, acquired immune diseases, gene and cell therapy, and transplantation.

Autoimmune diseases

Autoimmune diseases occur when immune responses of patients are directed against antigens produced from their own cells. There is a long list of autoimmune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, type 1 diabetes and systemic lupus erythematosus, all of which are caused by dysfunctions of the immune system. Despite a variety of therapeutic strategies being proposed,^94–99 many of these diseases are still managed with non-specific medications such as corticosteroids or chemotherapeutic drugs, which are associated with considerable adverse events.¹⁰⁰ Because DCs regulate both central and peripheral tolerance, they have been explored for treating autoimmune diseases using animal models.^101–104 The rationale of using DCs for treating autoimmune diseases has further been supported by the recent finding that constitutive ablation of DCs results in spontaneous fatal autoimmunity.¹⁰⁵ As the antigens involved in some of these diseases are known, it is feasible to generate antigen-specific tolerogenic DCs to treat these diseases. If antigen-specific tolerance can be established, there should be no major impact on host immune responses against tumour cells or microbial and viral infections.

Hypersensitivity diseases

Hypersensitivity diseases are also caused by unbalanced immune responses, but to foreign antigens, these diseases can be classified into type I, II, III and IV based on the types of antibodies or cells involved in mediation of the diseases. Because of space limitation, only type I hypersensitivity diseases will be used as an example to discuss the possible therapeutic application of tolerogenic DCs. A wide range of commonly occurring diseases, such as asthma and allergies, belong to type I hypersensitivity diseases. Patients with type I hypersensitivity over-react to certain common antigens in the environment by producing high levels of IgE antibodies although these antigens do not cause immune responses in healthy individuals. The immune responses to allergens in these patients are deviated towards T helper type 2 responses. Therefore, antigen-specific tolerance can be potentially generated with tolerogenic DCs.

Gene and cell therapy

Gene and cell therapies hold great potential for treatment of human diseases.^106–108 For gene therapy, host immune responses against gene therapy vectors are one of the barriers to its clinical applications. Potentially, therapeutic gene products can be immunogenic as well. Viral vectors are in general more efficient for gene delivery. Although most advanced viral vectors do not express viral genes, repeated administration still leads to a decrease in transgene expression and an increase in the immune responses against the vector. Hence, there is a need to induce antigen-specific tolerance towards viral vectors without compromising immunity towards wild-type virus. A general tolerance induction is not safe because patients need immunity against infection and tumour formation. The induction of vector-specific tolerance will be a major breakthrough because it will mitigate the current problem associated with re-administration of gene therapy vectors. For cell therapy, if non-self cells are used, alloantigens from donor cells will induce immune responses. Even if autologous cells are used, if cells need gene-correction, the therapeutic gene may cause problems. Therefore, antigen-specific tolerance can be useful for enhancing cell therapy.

Transplantation

In transplantation, alloantigens from donor cells can be presented to recipient T cells in at least three different pathways, direct, indirect and semi-direct.^109,110 The direct pathway involves donor DCs in grafts presenting antigens to recipient T cells whereas the indirect pathway involves recipient DCs presenting donor antigens to recipient T cells. Donor MHC complexes can be transferred from donor DCs to recipient DCs through exsomomes or membrane contacts and presentation of alloantigens in this way is called a semi-direct pathway.^109,111 Although there are no human studies reported for the successful application of DCs in transplantation, many transplantation studies using rodent models showed that modified DCs can efficiently enhance graft survival.^111–117 The potential of using tolerogenic DCs in transplantation is enormous, but more research is needed to translate the success of using tolerogenic DCs in rodent models into human applications.

Challenges to the therapeutic development

There are many hurdles to be overcome before tolerogenic DCs can be used in clinical applications. These challenges include defining the nature of DCs to be used for a particular application, standardizing protocols for their generation, identifying the optimal route for their delivery, and translating the success obtained with rodent models into human applications. However, none of these challenges are insurmountable.

First, to achieve consistent tolerogenic effects for a particular application, it will be important to define qualitative and quantitative characteristics for a type of DCs to be used for a particular application. As DCs are heterogeneous and display different cell surface markers in different tissues, it is unlikely that a single set of surface markers can be used to standardize the tolerogenic DCs for different applications. It is generally believed that immature DCs induce tolerance. However, how to sustain the immature state of DCs, especially after in vivo delivery, remains a challenge. Therefore, it is important to identify experimentally the type of DCs with the best tolerogenic ability for a particular application and to define their surface markers qualitatively and quantitatively. Currently, little has been done in this area.

Second, the methods for generation of tolerogenic DCs have to be standardized. The DCs can be generated ex vivo from progenitor cells of different tissue sources such as bone marrow, peripheral blood and perhaps induced pluripotent stem cells¹¹⁸ as well. In addition to the source of progenitor cells, there are different protocols using different growth factors for generating DCs. Traditionally, most studies use GM-CSF and IL-4 to generate DCs from precursor cells from bone marrow or blood⁵⁶ whereas newer protocols use the Flt3L.⁵⁷ Furthermore, the amount of antigens to be loaded should also be optimized because this may affect the behaviour of DCs. For some applications, the antigens may need to be identified first. Without the precise information on antigens, it is unlikely that antigen-specific tolerogenic DCs can be generated.

Third, methods for delivery of tolerogenic DCs have to be defined. Although it is known that DCs can be delivered though different routes, such as intravenous or subcutaneous injections into mice^28,119 or humans,¹²⁰ the efficiency of the delivered DCs reaching their destinations is very low. When DCs are delivered intravenously into mice, both mature and immature DCs can reach the spleen at the efficiency of 1–1·5%.²⁸ Interestingly, the delivered cells can home to the thymus, but at a much lower efficiency. A large portion of DCs delivered do not reach their destinations, so their effect on the immune system needs to be clarified. It is likely that DCs delivered through different routes will show differences in homing efficiency to different tissues. This will influence their tolerogenic effects on different organ systems. Information on DC migration in vivo is scarce and little is known about which route of DC delivery should be used for which type of application. In addition, the amount of DCs to be used for a particular application to achieve the optimal effect remains to be determined. DCs in tissues are likely interacting with other cells. It is also not known what changes might occur when DCs are delivered.

In addition, most studies on tolerogenic DCs have been performed in rodents and more studies are needed to translate the experimental success in rodent models into human applications. Although rodents and humans share great similarities in immunology, there are major differences in the cell biology of organs. For example, the lung airway epithelium in mice and humans is quite different. Mouse airway epithelium contains a large population of non-ciliated, non-mucous secretion cells, called Clara cells, which secrete a 10 kDa molecular weight protein (CC10) that has anti-inflammatory effects.^121,122 On the other hand, the human lung airway contains only a small percentage of Clara cells located at the terminal bronchioles.¹²³ As this difference in cell biology is expected to affect the local cytokine environment, it will influence the innate and adaptive immune responses locally. Therefore, therapeutic strategies for human applications have to reflect this type of difference.

Finally, commercialization of tolerogenic DCs could also be a challenge because this type of medication will be expensive to manufacture. However, as DC biology advances and protocols for producing tolerogenic DCs become standardized, hospital laboratories may be able to provide the service as long as the cost can be absorbed by the health-care system of the jurisdiction.

Concluding remarks

Considerable progress has been made in our understanding of DCs: their development, behaviour and function. Importantly, DCs can be generated in culture from precursors of different tissue sources. Studies in animals have demonstrated the enormous potential of using tolerogenic DCs for treating a variety of immune-imbalanced diseases as well as for enhancing future gene and cell therapies. This potential can be realized only when all the major challenges are overcome with more intensive experimental investigations.

Acknowledgement

J.H. and Y.W. have been supported by grants from the Canadian Institutes of Health Research.

Disclosures

The authors declare no financial or conflict of interest.

References

1 Steinman RM. Dendritic cells: understanding immunogenicity. Eur J Immunol 2007; 37(Suppl. 1): S53–60.
10.1002/eji.200737400
CASPubMedWeb of Science®Google Scholar
2 Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003; 21: 685–711.
10.1146/annurev.immunol.21.120601.141040
CASPubMedWeb of Science®Google Scholar
3 Bar-On L, Jung S. Defining dendritic cells by conditional and constitutive cell ablation. Immunol Rev 2010; 234: 76–89.
10.1111/j.0105-2896.2009.00875.x
CASPubMedWeb of Science®Google Scholar
4 Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science 2010; 327: 656–61.
10.1126/science.1178331
CASPubMedWeb of Science®Google Scholar
5 Liu K, Nussenzweig MC. Origin and development of dendritic cells. Immunol Rev 2010; 234: 45–54.
10.1111/j.0105-2896.2009.00879.x
CASPubMedWeb of Science®Google Scholar
6 Idoyaga J, Suda N, Suda K, Park CG, Steinman RM. Antibody to Langerin/CD207 localizes large numbers of CD8alpha⁺ dendritic cells to the marginal zone of mouse spleen. Proc Natl Acad Sci U S A 2009; 106: 1524–9.
10.1073/pnas.0812247106
CASPubMedWeb of Science®Google Scholar
7 Ginhoux F, Liu K, Helft J et al. The origin and development of nonlymphoid tissue CD103⁺ DCs. J Exp Med 2009; 206: 3115–30.
10.1084/jem.20091756
CASPubMedWeb of Science®Google Scholar
8 Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 2003; 19: 225–34.
10.1016/S1074-7613(03)00208-5
CASPubMedWeb of Science®Google Scholar
9 Corcoran L, Ferrero I, Vremec D et al. The lymphoid past of mouse plasmacytoid cells and thymic dendritic cells. J Immunol 2003; 170: 4926–32.
10.4049/jimmunol.170.10.4926
CASPubMedWeb of Science®Google Scholar
10 Tam MA, Wick MJ. Dendritic cells and immunity to Listeria: TipDCs are a new recruit. Trends Immunol 2004; 25: 335–9.
10.1016/j.it.2004.05.004
CASPubMedWeb of Science®Google Scholar
11 Aldridge JR Jr, Moseley CE, Boltz DA et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci U S A 2009; 106: 5306–11.
10.1073/pnas.0900655106
CASPubMedWeb of Science®Google Scholar
12 Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 2003; 19: 59–70.
10.1016/S1074-7613(03)00171-7
CASPubMedWeb of Science®Google Scholar
13 Dunay IR, Damatta RA, Fux B, Presti R, Greco S, Colonna M, Sibley LD. Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 2008; 29: 306–17.
10.1016/j.immuni.2008.05.019
CASPubMedWeb of Science®Google Scholar
14 Steiner G, Wolff K, Pehamberger H, Stingl G. Epidermal cells as accessory cells in the generation of allo-reactive and hapten-specific cytotoxic T lymphocyte (CTL) responses. J Immunol 1985; 134: 736–41.

PubMedWeb of Science®Google Scholar
15 Schuler G, Romani N, Steinman RM. A comparison of murine epidermal Langerhans cells with spleen dendritic cells. J Invest Dermatol 1985; 85: 99s–106s.
10.1111/1523-1747.ep12275566
CASPubMedWeb of Science®Google Scholar
16 Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med 1985; 161: 526–46.
10.1084/jem.161.3.526
CASPubMedWeb of Science®Google Scholar
17 Inaba K, Schuler G, Witmer MD, Valinksy J, Atassi B, Steinman RM. Immunologic properties of purified epidermal Langerhans cells. Distinct requirements for stimulation of unprimed and sensitized T lymphocytes. J Exp Med 1986; 164: 605–13.
10.1084/jem.164.2.605
PubMedWeb of Science®Google Scholar
18 Witmer-Pack MD, Olivier W, Valinsky J, Schuler G, Steinman RM. Granulocyte/macrophage colony-stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells. J Exp Med 1987; 166: 1484–98.
10.1084/jem.166.5.1484
CASPubMedWeb of Science®Google Scholar
19 Chorro L, Sarde A, Li M et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J Exp Med 2009; 206: 3089–100.
10.1084/jem.20091586
CASPubMedWeb of Science®Google Scholar
20 Ginhoux F, Merad M. Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 2010; 88: 387–92.
10.1038/icb.2010.38
PubMedWeb of Science®Google Scholar
21 Steinman RM, Witmer MD. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc Natl Acad Sci U S A 1978; 75: 5132–6.
10.1073/pnas.75.10.5132
CASPubMedWeb of Science®Google Scholar
22 Steinman RM, Gutchinov B, Witmer MD, Nussenzweig MC. Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice. J Exp Med 1983; 157: 613–27.
10.1084/jem.157.2.613
CASPubMedWeb of Science®Google Scholar
23 Liu K, Waskow C, Liu X, Yao K, Hoh J, Nussenzweig M. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat Immunol 2007; 8: 578–83.
10.1038/ni1462
CASPubMedWeb of Science®Google Scholar
24 Waskow C, Liu K, Darrasse-Jeze G et al. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat Immunol 2008; 9: 676–83.
10.1038/ni.1615
CASPubMedWeb of Science®Google Scholar
25 Park H, Li Z, Yang XO et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133–41.
10.1038/ni1261
CASPubMedWeb of Science®Google Scholar
26 Dong C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol 2006; 6: 329–33.
10.1038/nri1807
CASPubMedWeb of Science®Google Scholar
27 Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 2009; 9: 833–44.
10.1038/nri2669
CASPubMedWeb of Science®Google Scholar
28 Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol 2006; 7: 1092–100.
10.1038/ni1385
CASPubMedWeb of Science®Google Scholar
29 Proietto AI, van Dommelen S, Zhou P et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc Natl Acad Sci U S A 2008; 105: 19869–74.
10.1073/pnas.0810268105
CASPubMedWeb of Science®Google Scholar
30 Sakaguchi S. Naturally arising Foxp3-expressing CD25⁺ CD4⁺ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345–52.
10.1038/ni1178
CASPubMedWeb of Science®Google Scholar
31 Kurts C, Kosaka H, Carbone FR, Miller JF, Heath WR. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8⁺ T cells. J Exp Med 1997; 186: 239–45.
10.1084/jem.186.2.239
CASPubMedWeb of Science®Google Scholar
32 Probst HC, Lagnel J, Kollias G, van den Broek M. Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8⁺ T cell tolerance. Immunity 2003; 18: 713–20.
10.1016/S1074-7613(03)00120-1
CASPubMedWeb of Science®Google Scholar
33 Hawiger D, Inaba K, Dorsett Y et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 2001; 194: 769–79.
10.1084/jem.194.6.769
CASPubMedWeb of Science®Google Scholar
34 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: 626–35.
10.1016/j.immuni.2009.05.002
CASPubMedWeb of Science®Google Scholar
35 Saurer L, Mueller C. T cell-mediated immunoregulation in the gastrointestinal tract. Allergy 2009; 64: 505–19.
10.1111/j.1398-9995.2009.01965.x
CASPubMedWeb of Science®Google Scholar
36 Hadeiba H, Sato T, Habtezion A, Oderup C, Pan J, Butcher EC. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol 2008; 9: 1253–60.
10.1038/ni.1658
CASPubMedWeb of Science®Google Scholar
37 Liu K, Iyoda T, Saternus M, Kimura Y, Inaba K, Steinman RM. Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 2002; 196: 1091–7.
10.1084/jem.20021215
CASPubMedWeb of Science®Google Scholar
38 Lechler R, Chai JG, Marelli-Berg F, Lombardi G. The contributions of T-cell anergy to peripheral T-cell tolerance. Immunology 2001; 103: 262–9.
10.1046/j.1365-2567.2001.01250.x
CASPubMedWeb of Science®Google Scholar
39 Eroukhmanoff L, Oderup C, Ivars F. T-cell tolerance induced by repeated antigen stimulation: selective loss of Foxp3⁻ conventional CD4 T cells and induction of CD4 T-cell anergy. Eur J Immunol 2009; 39: 1078–87.
10.1002/eji.200838653
CASPubMedWeb of Science®Google Scholar
40 Qi H, Egen JG, Huang AY, Germain RN. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 2006; 312: 1672–6.
10.1126/science.1125703
CASPubMedWeb of Science®Google Scholar
41 Bergtold A, Desai DD, Gavhane A, Clynes R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 2005; 23: 503–14.
10.1016/j.immuni.2005.09.013
CASPubMedWeb of Science®Google Scholar
42 Koka R, Burkett P, Chien M, Chai S, Boone DL, Ma A. Cutting edge: murine dendritic cells require IL-15R alpha to prime NK cells. J Immunol 2004; 173: 3594–8.
10.4049/jimmunol.173.6.3594
CASPubMedWeb of Science®Google Scholar
43 Hochweller K, Striegler J, Hammerling GJ, Garbi N. A novel CD11c.DTR transgenic mouse for depletion of dendritic cells reveals their requirement for homeostatic proliferation of natural killer cells. Eur J Immunol 2008; 38: 2776–83.
10.1002/eji.200838659
CASPubMedWeb of Science®Google Scholar
44 Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 1998; 9: 669–76.
10.1016/S1074-7613(00)80664-0
CASPubMedWeb of Science®Google Scholar
45 Kennedy MK, Glaccum M, Brown SN et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 2000; 191: 771–80.
10.1084/jem.191.5.771
CASPubMedWeb of Science®Google Scholar
46 Plaks V, Birnberg T, Berkutzki T et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest 2008; 118: 3954–65.

CASPubMedWeb of Science®Google Scholar
47 Inaba K, Steinman RM, Pack MW, Aya H, Inaba M, Sudo T, Wolpe S, Schuler G. Identification of proliferating dendritic cell precursors in mouse blood. J Exp Med 1992; 175: 1157–67.
10.1084/jem.175.5.1157
CASPubMedWeb of Science®Google Scholar
48 Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman RM. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 1992; 176: 1693–702.
10.1084/jem.176.6.1693
CASPubMedWeb of Science®Google Scholar
49 Goxe B, Latour N, Chokri M, Abastado JP, Salcedo M. Simplified method to generate large quantities of dendritic cells suitable for clinical applications. Immunol Invest 2000; 29: 319–36.
10.3109/08820130009060870
CASPubMedWeb of Science®Google Scholar
50 Thomson AW. Tolerogenic dendritic cells: all present and correct? Am J Transplant 2010; 10: 214–9.
10.1111/j.1600-6143.2009.02955.x
CASWeb of Science®Google Scholar
51 Gilboa E. DC-based cancer vaccines. J Clin Invest 2007; 117: 1195–203.
10.1172/JCI31205
CASPubMedWeb of Science®Google Scholar
52 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783–801.
10.1016/j.cell.2006.02.015
CASPubMedWeb of Science®Google Scholar
53 Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004; 5: 987–95.
10.1038/ni1112
CASPubMedWeb of Science®Google Scholar
54 Martin-Fontecha A, Lanzavecchia A, Sallusto F. Dendritic cell migration to peripheral lymph nodes. Handb Exp Pharmacol 2009; 188, 31–49.
10.1007/978-3-540-71029-5_2
CASPubMedGoogle Scholar
55 Baumjohann D, Hess A, Budinsky L, Brune K, Schuler G, Lutz MB. In vivo magnetic resonance imaging of dendritic cell migration into the draining lymph nodes of mice. Eur J Immunol 2006; 36: 2544–55.
10.1002/eji.200535742
CASPubMedWeb of Science®Google Scholar
56 Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor-α. J Exp Med 1994; 179: 1109–18.
10.1084/jem.179.4.1109
CASPubMedWeb of Science®Google Scholar
57 Naik SH, Proietto AI, Wilson NS et al. Cutting edge: generation of splenic CD8⁺ and CD8⁻ dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J Immunol 2005; 174: 6592–7.
10.4049/jimmunol.174.11.6592
CASPubMedWeb of Science®Google Scholar
58 Steinman RM, Hawiger D, Liu K et al. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann N Y Acad Sci 2003; 987: 15–25.
10.1111/j.1749-6632.2003.tb06029.x
CASPubMedWeb of Science®Google Scholar
59 Rutella S, Danese S, Leone G. Tolerogenic dendritic cells: cytokine modulation comes of age. Blood 2006; 108: 1435–40.
10.1182/blood-2006-03-006403
CASPubMedWeb of Science®Google Scholar
60 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: 190–5.
10.1196/annals.1317.011
CASPubMedWeb of Science®Google Scholar
61 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: 6424–9.
10.1073/pnas.0912437107
CASPubMedWeb of Science®Google Scholar
62 Farquhar CA, Paterson AM, Cobbold SP et al. Tolerogenicity is not an absolute property of a dendritic cell. Eur J Immunol 2010; 40: 1728–37.
10.1002/eji.200939974
CASPubMedWeb of Science®Google Scholar
63 Kalinski P. Dendritic cells in immunotherapy of established cancer: roles of signals 1, 2, 3 and 4. Curr Opin Investig Drugs 2009; 10: 526–35.

CASPubMedWeb of Science®Google Scholar
64 Berger TG, Schulze-Koops H, Schafer M, Muller E, Lutz MB. Immature and maturation-resistant human dendritic cells generated from bone marrow require two stimulations to induce T cell anergy in vitro. PLoS ONE 2009; 4: e6645.
10.1371/journal.pone.0006645
CASPubMedWeb of Science®Google Scholar
65 Kim SH, Kim S, Evans CH, Ghivizzani SC, Oligino T, Robbins PD. Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4. J Immunol 2001; 166: 3499–505.
10.4049/jimmunol.166.5.3499
CASPubMedWeb of Science®Google Scholar
66 Lu L, Lee WC, Takayama T, Qian S, Gambotto A, Robbins PD, Thomson AW. Genetic engineering of dendritic cells to express immunosuppressive molecules (viral IL-10, TGF-β, and CTLA4Ig). J Leukoc Biol 1999; 66: 293–6.
10.1002/jlb.66.2.293
CASPubMedWeb of Science®Google Scholar
67 Yamazaki S, Bonito AJ, Spisek R, Dhodapkar M, Inaba K, Steinman RM. Dendritic cells are specialized accessory cells along with TGF-beta for the differentiation of Foxp3⁺ CD4⁺ regulatory T cells from peripheral Foxp3 precursors. Blood 2007; 110: 4293–302.
10.1182/blood-2007-05-088831
CASPubMedWeb of Science®Google Scholar
68 Dumitriu IE, Dunbar DR, Howie SE, Sethi T, Gregory CD. Human dendritic cells produce TGF-β1 under the influence of lung carcinoma cells and prime the differentiation of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells. J Immunol 2009; 182: 2795–807.
10.4049/jimmunol.0712671
CASPubMedWeb of Science®Google Scholar
69 Lee WC, Qiani S, Wan Y et al. Contrasting effects of myeloid dendritic cells transduced with an adenoviral vector encoding interleukin-10 on organ allograft and tumour rejection. Immunology 2000; 101: 233–41.
10.1046/j.1365-2567.2000.00096.x
CASPubMedWeb of Science®Google Scholar
70 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: 1162–9.
10.1182/blood-2004-03-1211
CASPubMedWeb of Science®Google Scholar
71 Kim SH, Bianco N, Menon R, Lechman ER, Shufesky WJ, Morelli AE, Robbins PD. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol Ther 2006; 13: 289–300.
10.1016/j.ymthe.2005.09.015
CASPubMedWeb of Science®Google Scholar
72 Bohana-Kashtan O, Civin CI. Fas ligand as a tool for immunosuppression and generation of immune tolerance. Stem Cells 2004; 22: 908–24.
10.1634/stemcells.22-6-908
CASPubMedWeb of Science®Google Scholar
73 Yang DF, Qiu WH, Zhu HF, Lei P, Wen X, Dai H, Zhou W, Shen GX. CTLA4-Ig-modified dendritic cells inhibit lymphocyte-mediated alloimmune responses and prolong the islet graft survival in mice. Transpl Immunol 2008; 19: 197–201.
10.1016/j.trim.2008.05.005
CASPubMedWeb of Science®Google Scholar
74 Bianco NR, Kim SH, Ruffner MA, Robbins PD. Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models. Arthritis Rheum 2009; 60: 380–9.
10.1002/art.24229
CASPubMedWeb of Science®Google Scholar
75 Hirata S, Senju S, Matsuyoshi H, Fukuma D, Uemura Y, Nishimura Y. Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cell-derived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed death-1 ligand. J Immunol 2005; 174: 1888–97.
10.4049/jimmunol.174.4.1888
CASPubMedWeb of Science®Google Scholar
76 Hill JA, Ichim TE, Kusznieruk KP et al. Immune modulation by silencing IL-12 production in dendritic cells using small interfering RNA. J Immunol 2003; 171: 691–6.
10.4049/jimmunol.171.2.691
CASPubMedWeb of Science®Google Scholar
77 Lee JI, Ganster RW, Geller DA, Burckart GJ, Thomson AW, Lu L. Cyclosporine A inhibits the expression of costimulatory molecules on in vitro-generated dendritic cells: association with reduced nuclear translocation of nuclear factor-κB. Transplantation 1999; 68: 1255–63.
10.1097/00007890-199911150-00007
CASPubMedWeb of Science®Google Scholar
78 Yang J, Bernier SM, Ichim TE et al. LF15-0195 generates tolerogenic dendritic cells by suppression of NF-κB signaling through inhibition of IKK activity. J Leukoc Biol 2003; 74: 438–47.
10.1189/jlb.1102582
CASPubMedWeb of Science®Google Scholar
79 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: 3147–59.
10.1002/eji.200839103
CASPubMedWeb of Science®Google Scholar
80 Pothoven KL, Kheradmand T, Yang Q, Houlihan JL, Zhang H, Degutes M, Miller SD, Luo X. Rapamycin-conditioned donor dendritic cells differentiate CD4CD25Foxp3 T cells in vitro with TGF-β1 for islet transplantation. Am J Transplant 2010; 10: 1774–84.
10.1111/j.1600-6143.2010.03199.x
CASPubMedWeb of Science®Google Scholar
81 Raimondi G, Sumpter TL, Matta BM, Pillai M, Corbitt N, Vodovotz Y, Wang Z, Thomson AW. Mammalian target of rapamycin inhibition and alloantigen-specific regulatory T cells synergize to promote long-term graft survival in immunocompetent recipients. J Immunol 2010; 184: 624–36.
10.4049/jimmunol.0900936
CASPubMedWeb of Science®Google Scholar
82 Turnquist HR, Raimondi G, Zahorchak AF, Fischer RT, Wang Z, Thomson AW. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4⁺ T cells, but enrich for antigen-specific Foxp3⁺ T regulatory cells and promote organ transplant tolerance. J Immunol 2007; 178: 7018–31.
10.4049/jimmunol.178.11.7018
CASPubMedWeb of Science®Google Scholar
83 van de Laar L, Buitenhuis M, Wensveen FM, Janssen HL, Coffer PJ, Woltman AM. Human CD34-derived myeloid dendritic cell development requires intact phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin signaling. J Immunol 2010; 184: 6600–11.
10.4049/jimmunol.0903089
CASPubMedWeb of Science®Google Scholar
84 Woltman AM, de Fijter JW, Kamerling SW, van Der Kooij SW, Paul LC, Daha MR, van Kooten C. Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages. Blood 2001; 98: 174–80.
10.1182/blood.V98.1.174
CASPubMedWeb of Science®Google Scholar
85 Haidinger M, Poglitsch M, Geyeregger R et al. A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J Immunol 2010; 185: 3919–31.
10.4049/jimmunol.1000296
CASPubMedWeb of Science®Google Scholar
86 Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL Jr, Eissa NT. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 2009; 15: 267–76.
10.1038/nm.1928
CASPubMedWeb of Science®Google Scholar
87 Mukhopadhaya A, Hanafusa T, Jarchum I et al. Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8⁺ T cells in NOD mice. Proc Natl Acad Sci U S A 2008; 105: 6374–9.
10.1073/pnas.0802644105
PubMedWeb of Science®Google Scholar
88 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: 6923–33.
10.4049/jimmunol.181.10.6923
CASPubMedWeb of Science®Google Scholar
89 Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 1998; 188: 1359–68.
10.1084/jem.188.7.1359
CASPubMedWeb of Science®Google Scholar
90 Chen M, Wang YH, Wang Y, Huang L, Sandoval H, Liu YJ, Wang J. Dendritic cell apoptosis in the maintenance of immune tolerance. Science 2006; 311: 1160–4.
10.1126/science.1122545
CASPubMedWeb of Science®Google Scholar
91 Lu Q, Lemke G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 2001; 293: 306–11.
10.1126/science.1061663
CASPubMedWeb of Science®Google Scholar
92 Wallet MA, Sen P, Flores RR et al. MerTK is required for apoptotic cell-induced T cell tolerance. J Exp Med 2008; 205: 219–32.
10.1084/jem.20062293
CASPubMedWeb of Science®Google Scholar
93 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: 7104–18.
10.4049/jimmunol.0900824
CASPubMedWeb of Science®Google Scholar
94 Fleischmann RM. Safety of biologic therapy in rheumatoid arthritis and other autoimmune diseases: focus on rituximab. Semin Arthritis Rheum 2009; 38: 265–80.
10.1016/j.semarthrit.2008.01.001
CASPubMedWeb of Science®Google Scholar
95 Sharabi A, Mozes E. Harnessing regulatory T cells for the therapy of lupus and other autoimmune diseases. Immunotherapy 2009; 1: 385–401.
10.2217/imt.09.2
CASPubMedWeb of Science®Google Scholar
96 Leung PS, Dhirapong A, Wu PY, Tao MH. Gene therapy in autoimmune diseases: challenges and opportunities. Autoimmun Rev 2010; 9: 170–4.
10.1016/j.autrev.2009.10.004
CASPubMedWeb of Science®Google Scholar
97 Bach JF. Immunosuppressive therapy of autoimmune diseases. Immunol Today 1993; 14: 322–6.
10.1016/0167-5699(93)90053-N
CASPubMedWeb of Science®Google Scholar
98 Furlan R, Butti E, Pluchino S, Martino G. Gene therapy for autoimmune diseases. Curr Opin Mol Ther 2004; 6: 525–36.

CASPubMedWeb of Science®Google Scholar
99 Dazzi F, van Laar JM, Cope A, Tyndall A. Cell therapy for autoimmune diseases. Arthritis Res Ther 2007; 9: 206.
10.1186/ar2128
CASPubMedWeb of Science®Google Scholar
100 Pascual V, Chaussabel D, Banchereau J. A genomic approach to human autoimmune diseases. Annu Rev Immunol 2010; 28: 535–71.
10.1146/annurev-immunol-030409-101221
CASPubMedWeb of Science®Google Scholar
101 Bruder D, Westendorf AM, Hansen W et al. On the edge of autoimmunity: T-cell stimulation by steady-state dendritic cells prevents autoimmune diabetes. Diabetes 2005; 54: 3395–401.
10.2337/diabetes.54.12.3395
CASPubMedWeb of Science®Google Scholar
102 Xiao BG, Huang YM, Link H. Dendritic cell vaccine design: strategies for eliciting peripheral tolerance as therapy of autoimmune diseases. BioDrugs 2003; 17: 103–11.
10.2165/00063030-200317020-00003
CASPubMedWeb of Science®Google Scholar
103 Khoury SJ, Gallon L, Chen W et al. Mechanisms of acquired thymic tolerance in experimental autoimmune encephalomyelitis: thymic dendritic-enriched cells induce specific peripheral T cell unresponsiveness in vivo. J Exp Med 1995; 182: 357–66.
10.1084/jem.182.2.357
CASPubMedWeb of Science®Google Scholar
104 Feili-Hariri M, Flores RR, Vasquez AC, Morel PA. Dendritic cell immunotherapy for autoimmune diabetes. Immunol Res 2006; 36: 167–73.
10.1385/IR:36:1:167
CASPubMedWeb of Science®Google Scholar
105 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: 549–59.
10.1084/jem.20082394
CASPubMedWeb of Science®Google Scholar
106 Flotte TR, Ng P, Dylla DE, McCray PB Jr, Wang G, Kolls JK, Hu J. Viral vector-mediated and cell-based therapies for treatment of cystic fibrosis. Mol Ther 2007; 15: 229–41.
10.1038/sj.mt.6300002
CASPubMedWeb of Science®Google Scholar
107 Colella P, Cotugno G, Auricchio A. Ocular gene therapy: current progress and future prospects. Trends Mol Med 2009; 15: 23–31.
10.1016/j.molmed.2008.11.003
CASPubMedWeb of Science®Google Scholar
108 Richardson RM, Varenika V, Forsayeth JR, Bankiewicz KS. Future applications: gene therapy. Neurosurg Clin N Am 2009; 20: 205–10.
10.1016/j.nec.2009.04.004
CASPubMedWeb of Science®Google Scholar
109 Herrera OB, Golshayan D, Tibbott R, Salcido Ochoa F, James MJ, Marelli-Berg FM, Lechler RI. A novel pathway of alloantigen presentation by dendritic cells. J Immunol 2004; 173: 4828–37.
10.4049/jimmunol.173.8.4828
CASPubMedWeb of Science®Google Scholar
110 Gould DS, Auchincloss H Jr. Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol Today 1999; 20: 77–82.
10.1016/S0167-5699(98)01394-2
CASPubMedWeb of Science®Google Scholar
111 Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 2007; 7: 610–21.
10.1038/nri2132
CASPubMedWeb of Science®Google Scholar
112 Ali A, Garrovillo M, Jin MX, Hardy MA, Oluwole SF. Major histocompatibility complex class I peptide-pulsed host dendritic cells induce antigen-specific acquired thymic tolerance to islet cells. Transplantation 2000; 69: 221–6.
10.1097/00007890-200001270-00005
CASPubMedWeb of Science®Google Scholar
113 Ali A, Garrovillo M, Oluwole OO, Depaz HA, Gopinathan R, Engelstad K, Hardy MA, Oluwole SF. Mechanisms of acquired thymic tolerance: induction of transplant tolerance by adoptive transfer of in vivo alloMHC peptide activated syngeneic T cells. Transplantation 2001; 71: 1442–8.
10.1097/00007890-200105270-00015
CASPubMedWeb of Science®Google Scholar
114 Garrovillo M, Ali A, Oluwole SF. Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host dendritic cells. Transplantation 1999; 68: 1827–34.
10.1097/00007890-199912270-00001
CASPubMedWeb of Science®Google Scholar
115 Garrovillo M, Ali AO, DePaz HA, Gopinathan R, Oluwole OO, Hardy MA, Oluwole SF. Regulatory role of the thymic dendritic cells in acquired thymic tolerance: induction of tolerance to cardiac allografts by adoptive transfer of allopeptide-pulsed host thymic dendritic cells. Transplant Proc 2001; 33: 149.
10.1016/S0041-1345(00)01948-5
CASPubMedWeb of Science®Google Scholar
116 Oluwole OO, Depaz HA, Gopinathan R, Ali A, Garrovillo M, Jin MX, Hardy MA, Oluwole SF. Indirect allorecognition in acquired thymic tolerance: induction of donor-specific permanent acceptance of rat islets by adoptive transfer of allopeptide-pulsed host myeloid and thymic dendritic cells. Diabetes 2001; 50: 1546–52.
10.2337/diabetes.50.7.1546
CASPubMedWeb of Science®Google Scholar
117 Mirenda V, Berton I, Read J, Cook T, Smith J, Dorling A, Lechler RI. Modified dendritic cells coexpressing self and allogeneic major histocompatability complex molecules: an efficient way to induce indirect pathway regulation. J Am Soc Nephrol 2004; 15: 987–97.
10.1097/01.ASN.0000119575.98696.1D
CASPubMedWeb of Science®Google Scholar
118 Senju S, Matsunaga Y, Fukushima S, Hirata S, Matsuyoshi H, Nishimura Y. Pluripotent stem cell-derived dendritic cells for immunotherapy. Front Biosci (Elite Ed) 2010; 2: 1520–7.
10.2741/E211
PubMedGoogle Scholar
119 Nair S, McLaughlin C, Weizer A, Su Z, Boczkowski D, Dannull J, Vieweg J, Gilboa E. Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J Immunol 2003; 171: 6275–82.
10.4049/jimmunol.171.11.6275
CASPubMedWeb of Science®Google Scholar
120 De Vries IJ, Krooshoop DJ, Scharenborg NM et al. Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res 2003; 63: 12–7.

CASPubMedWeb of Science®Google Scholar
121 Lensmar C, Nord M, Gudmundsson GH et al. Decreased pulmonary levels of the anti-inflammatory Clara cell 16 kDa protein after induction of airway inflammation in asthmatics. Cell Mol Life Sci 2000; 57: 976–81.
10.1007/PL00000738
CASPubMedWeb of Science®Google Scholar
122 Katavolos P, Ackerley CA, Viel L, Clark ME, Wen X, Bienzle D. Clara cell secretory protein is reduced in equine recurrent airway obstruction. Vet Pathol 2009; 46: 604–13.
10.1354/vp.08-VP-0255-B-FL
CASPubMedWeb of Science®Google Scholar
123 Plopper CG, Hill LH, Mariassy AT. Ultrastructure of the nonciliated bronchiolar epithelial (Clara) cell of mammalian lung. III. A study of man with comparison of 15 mammalian species. Exp Lung Res 1980; 1: 171–80.
10.3109/01902148009069646
CASPubMedWeb of Science®Google Scholar

Citing Literature

Volume132, Issue3

March 2011

Pages 307-314

Tolerogenic dendritic cells and their potential applications

Summary

Introduction

DC functions

Generation of antigen-specific immune responses

Generation of antigen-specific tolerance

Modulation of functions of other cells

In vitro generation of tolerogenic DCs

Growth factor-engendered immature DCs

Genetically modified immature DCs

Immunosuppressive drug-induced tolerogenic DCs

Potential applications of tolerogenic DCs

Autoimmune diseases

Hypersensitivity diseases

Gene and cell therapy

Transplantation

Challenges to the therapeutic development

Concluding remarks

Acknowledgement

Disclosures

References

Citing Literature

References

Information

About Wiley Online Library

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Tolerogenic dendritic cells and their potential applications

Summary

Introduction

DC functions

Generation of antigen-specific immune responses

Generation of antigen-specific tolerance

Modulation of functions of other cells

In vitro generation of tolerogenic DCs

Growth factor-engendered immature DCs

Genetically modified immature DCs

Immunosuppressive drug-induced tolerogenic DCs

Potential applications of tolerogenic DCs

Autoimmune diseases

Hypersensitivity diseases

Gene and cell therapy

Transplantation

Challenges to the therapeutic development

Concluding remarks

Acknowledgement

Disclosures

References

Citing Literature

References

Related

Information