Dendritic Cells in Autoimmune Disease

Chapter 12

Dendritic Cells in Autoimmune Disease Kristen Radford1, Ken Shortman2,3, and Meredith O’Keeffe3,4 1

Cancer Immunotherapies Group, Mater Medical Research Institute, South Brisbane, Australia, 2Immunology Division, The Walter and Eliza Hall

Institute, Parkville, Australia and Centre for Immunology, Burnet Institute, Melbourne, Victoria, Australia, 3Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia, 4Department of Immunology, Monash University, Clayton, Victoria, Australia

Chapter Outline Antigen Processing by Dendritic Cells Pattern Recognition Receptors Dendritic Cell Activation Dendritic Cell Subsets Mouse Dendritic Cells Dendritic Cells in the Mouse Thymus DC Subsets and Tolerance Human DC subsets in Steady State DC subsets in Human Skin: Epidermal Langerhans Cells and Dermal DC

175 176 176 176 176 179 179 180

DC and Autoimmune Disease Systemic Lupus Erythematosus IBD—Crohn’s Disease and Ulcerative Colitis DC Immunotherapy as a Treatment for Autoimmune Diseases Targeting of DC in Autoimmune Disease Conclusions and Future Prospects References

181 181 182 182 182 183 183

180

ANTIGEN PROCESSING BY DENDRITIC CELLS Dendritic cells (DC) take up antigenic material, soluble and particulate, self and foreign, by a variety of processes including phagocytosis, pinocytosis and receptor mediated endocytosis. Some DC are equipped with receptors for recognition of apoptotic or necrotic cells of the body (Sancho et al., 2009; Zhang et al., 2012). Non-activated (“immature”) DC are especially active in antigen uptake; some uptake processes are shut off once the DC become activated (“mature”). In contrast to other phagocytic cells such as macrophages that rapidly and completely degrade phagocytosed material, DC conserve antigenic material for a prolonged period, allowing continuous processing and presentation of antigen. There are several antigenprocessing routes in DC (Trombetta and Mellman, 2005; Wilson and Villadangos, 2005). Exogenous antigens are usually processed in endocytic vesicles, leading to appropriate peptides being loaded onto major histocompatibility complex (MHC) class II molecules. The MHC class II associated antigens then presented to CD4 T cells will include peptides from exogenous foreign antigens, along

with peptides from self components such as recycling DC surface molecules. When conventional DC are activated, the MHC class II peptide complexes all shift to the cell surface and are no longer recycled, so for their limited lifespan the mature DC present a “snapshot” of the antigenic environment at the time of activation. DC, along with most other cells, produce, as a byproduct of protein synthesis, peptides that are loaded onto MHC class I for presentation to CD8 T cells. Such endogenously derived “self” antigens will include viral antigens if the DC are infected with a virus. Some DC have the additional ability to take up and shuttle exogenous antigens into the MHC class I presentation pathway. This specialized function is only performed efficiently by particular DC subtypes, and has been termed “crosspresentation” (Heath et al., 2004). Cross-presentation of exogenous antigens, including material from dead cells, is important for the generation of cytotoxic T cell responses to intracellular pathogens that do not infect the DC themselves. The pathways of cross-presentation are still being determined, but involve movement of antigen from the endocytic vesicles through the cytosol into the endoplasmic reticulum to join the MHC class I loading pathway.

N. Rose & I. Mackay (Eds): The Autoimmune Diseases, Fifth edition. DOI: http://dx.doi.org/10.1016/B978-0-12-384929-8.00012-5 © 2014 Elsevier Inc. All rights reserved.

175

176

Only some DC subsets cross-present antigens efficiently and this capacity is induced as a late step in their development (Shortman and Heath, 2010).

PATTERN RECOGNITION RECEPTORS A unifying feature of all DC is the expression of receptors that recognize microbial products or damaged cells, aspects of the environment often generalized as “danger.” These receptors, collectively called pattern recognition receptors (PRR) are not all expressed on all DC subsets and indeed the differential expression of PRR is a major functional discriminator of DC subsets (Hochrein and O’Keeffe, 2008; Table 12.1). PRRs exist on the plasma membrane, in the cytoplasm, and on endosomal membranes of cells. They belong to four major families: Toll-like receptors (TLR) 1 13; Rig-like helicases (RLH); C-type lectin receptors; and nucleotide-binding domain, leucine-rich repeat containing (NLR) receptors. The PRRs recognize a variety of pathogen-derived and self molecules. For recent reviews see: TLR (Uematsu and Akira, 2008; Kawai and Akira, 2010, 2011); NLR (Martinon and Tschopp, 2005, Davis et al., 2011; Elinav et al., 2011); RLH (Barbalat et al., 2011; Loo and Gale Jr., 2011); C-type lectin receptors (Robinson et al., 2006; Diebold, 2009; Kerrigan and Brown, 2009; Osorio and Reis e Sousa, 2011). Most importantly, not all DC express all receptors and in fact there is heterogeneity in the expression of the different receptor families. Particularly relevant for vaccine design, adjuvants induce different immune responses and this is mediated at least in part by the fact that different adjuvants work through different PRR and target different subsets of immune cells such as DC. Likewise, PRR activation in autoimmune disease may involve activation of discrete DC subsets exemplified by the activation of plasmacytoid DC (pDC) in patients with lupus (see below). It is important to note that the pattern of expression of PRR is not always the same between similar cells of different species and thus caution must be taken in interpreting effects of ligation of different PRR in animal models of disease and their relevance to human disease settings.

DENDRITIC CELL ACTIVATION The engagement of PRR provides signals that are needed to activate DC to full immunogenic function. The signaling pathways downstream of PRR all converge on the activation of the transcription factor family NF-κB, leading to the production of cytokines and the upregulation of costimulator molecules and MHC molecules on the DC surface (Kawai and Akira, 2007; Diebold, 2009).

PART | 3

Non-Antigen-Specific Recognition

DENDRITIC CELL SUBSETS DC can be divided into two major categories; conventional (c) DC (sometimes termed myeloid DC) and plasmacytoid (p) DC (sometimes termed lymphoid DC). The cDC can be further divided into migratory and resident subsets based upon tissue location and surface phenotype (Table 12.1: DC subsets, location, PRR expression, known cytokine production). The migratory DC collect antigen in peripheral tissues then migrate to lymph nodes for presentation to T cells. The lymphoid tissue resident DC collect antigen within the lymphoid organs, either directly or as antigen acquired from other cell types including migratory DC. It is also useful to distinguish the DC found in normal, healthy “steady-state” from activated “inflammatory” DC that are generated, sometimes in substantial numbers, in response to inflammation or infection. Inflammatory DC can develop from monocytes; they are modeled by the development of DC in culture when monocytes are cultured with cytokines including GM-CSF, although recent reports suggest that M-CSF may actually be the crucial growth factor required by these DC (Greter et al., 2012). The most detailed information on individual DC subsets comes from studies on laboratory mice. Although the general picture translates to the human immune system, many of the details of surface markers and specialized functions differ, so mouse and human DC subsets will be discussed separately.

MOUSE DENDRITIC CELLS Mouse spleen, lacking input from the lymphatics, serves as an enriched source of resident DC (Table 12.1). CD8α has been a useful marker in mice for distinguishing resident cDC subsets, although its function is unknown and it is not expressed on human DC. The CD8α1 cDC, as well as having the unifying DC function of presenting exogenous antigens on MHC class II, have the additional capacity for “cross-presentation,” i.e., the ability to present exogenous antigen in the context of MHC class I (Villadangos and Schnorrer, 2007). Accordingly, CD81 cDC are particularly efficient at inducing CD81 T cells in response to exogenous antigens. High IL-12p70 production on activation via PRR is another hallmark of CD8α1 cDC (Reis e Sousa et al., 1997; Maldonado-Lopez et al., 1999; Hochrein et al., 2001) and this leads to a capacity to bias activated T cells to an inflammatory Th1 response. The CD81 DC express high levels of TLR3, recognizing dsRNA, and TLR9, recognizing ssDNA, both located in intracellular endosomes. These PRR equip the CD81 DC to respond to viral and bacterial nucleic acids. The CD81 cDC are also especially efficient in the uptake of dead and dying cells. One PRR involved in dead cell recognition by

TABLE 12.1 Pattern Recognition Receptors Expressed by Mouse DC Conventional DC CD81

CD82

pDC

Toll-like Receptors TLR1

Plasma membrane

Triacyl lipoprotein

Bacteria

ü

ü

ü

TLR2

Plasma membrane

Lipoprotein

Bacteria, viruses, parasites

ü

ü

ü

TLR3

Endolysosome

dsRNA

Virus, mammals

ü

1/ 2

X

TLR4

Plasma membrane

LPS

Bacteria, viruses

ü

ü

X

TLR5

Plasma membrane

Flagellin

Bacteria

X

ü subset

X

TLR6

Plasma membrane

Diacyl lipoprotein

Bacteria, viruses

ü

ü

ü

TLR7

Endolysosome

ssRNA

Virus, bacteria, mammals

X

ü

ü

TLR9

Endolysosome

CpG DNA

Virus, bacteria, protozoa, mammals

ü

ü

ü

TLR11

Plasma membrane

Profilin-like molecule

Protozoa

ü

X

X

RIG-1

Cytoplasm

Short ds RNA

RNA viruses, DNA virus

X

ü

1/ 2

MDA5

Cytoplasm

Long ds RNA

RNA viruses

X

ü

1/ 2

Cytoplasm

g-D-glutamyl-meso-diaminopimelic acid (iE-DAP)

Bacteria

1/2

ü

1/ 2

CD205

Plasma membrane

Unknown but used successfully for DC targeting

X

X

ü

Clec9A

Plasma membrane

Dead cells of self origin

ü

X

ü

Rig-like Helicases

NOD-like Receptors NOD-1 C-type Lectins

Selected pattern recognition receptors, their cellular location, and specificity are shown along with their pattern of expression in the DC subsets of mouse spleen. 1/2 depicts low or weak expression.

178

CD81 DC is Clec9A, which recognizes the filamentous form of actin (F actin), exposed when the membrane of a cell is disrupted (Sancho et al., 2009; Zhang et al., 2012). With the dual functions of cross-presentation and dead cell uptake, the CD81 DC are perfectly equipped to present viral and bacterial antigens from infected dead and dying cells. Moreover, it is not hard to imagine that in an autoimmune setting the CD81 DC could be particularly detrimental as they may be activated by self nucleic acids taken up in dead cells and present self peptides present in these cells, leading to activation of cytotoxic T cells. The CD82 lymphoid tissue resident cDC are more numerous than the CD81 cDC, but recent evidence indicates they consist of two distinct DC subsets separable by expression of several markers including Clec12A, DCIR2, and CD4 (Kasahara and Clark, 2012). However, most functional data so far relate to the unseparated CD82 DC population. All cDC are capable of presenting antigen to CD41 T cells via MHC class II but the CD82 cDC are the most efficient. T cell activation driven by activated CD82 DC may lead to a Th2 response, possibly due to the DCIR2 DC subset. The CD82 cDC express TLR7 (recognizes ssRNA), TLR9, and very high levels of intracellular Rig-like helicase receptors (RLR) that recognize dsRNA in the cytoplasm (Luber et al., 2010). The high expression of RLR and some NLR (Luber et al., 2010), suggests that the CD82 cDC are particularly primed to rapidly respond to intracellular viral and bacterial infection. The CD82 cDC express high levels of chemokines including CCL5 (RANTES), CCL3 (MIP-1α), and CCL4 (MIP-1β). These chemokines are elevated upon PRR activation but are also expressed constitutively by CD82 cDC (Proietto et al., 2004). Lymph nodes, as well as containing similar resident cDC to spleen, also contain migratory DC even in steady state, but the input from peripheral tissues increases markedly on infection or inflammation. These DC that have migrated in from peripheral tissues are more mature than the resident DC in terms of costimulator molecule expression even in the steady state, but are not necessarily immunogenic and do not produce cytokines unless they have received the appropriate PRR signals. Three basic types of migratory DC have been identified (Bursch et al., 2007; Poulin et al., 2007). Langerhans cells in the skin epidermis were identified long before their function as DC was recognized (Merad et al., 2008). They have an exceptionally long lifespan in the epidermis, but turn over rapidly post migration. Recent work suggests they have a predominantly tolerogenic role, even in an activated state (Shklovskaya et al., 2011). DC resembling Langerhans cells also occur in other epithelial tissues. A more rapidly migrating DC population occurs in the skin dermis

PART | 3

Non-Antigen-Specific Recognition

and as interstitial DC in other tissues. Recently a minor but important migratory DC subset was discovered in the skin dermis and in other tissues, first distinguished by expression of CD103 and sharing with Langerhans cells the expression of langerin, a pathogen recognition molecule expressed at high levels in Langerhans cells but also at lower levels in some other DC (Nagao et al., 2009). However, this numerically minor DC subset, although not expressing CD8, is similar in functional properties to the resident CD81 DC subset in expressing Clec9A, in processing material from dead cells and in a marked capacity for cross-presentation. It may be considered as the migratory counterpart of the resident CD81 cDC. The pDC are generally considered as part of the DC “family” but in many respects have similarities to B cells. pDC circulate through the bloodstream much like lymphocytes and have a lymphocyte-like morphology. pDC also normally lack the ability to stimulate naı¨ve T cells (O’Keeffe et al., 2002). The categorization of the pDC as a member of the DC “family” rests upon morphological and phenotypical features that they display upon activation, when the pDC upregulate costimulation markers and MHC molecules to levels resembling the cDC and rapidly acquire the typical stellate morphology of cDC. The pDC express high levels of TLR7 and TLR9. If given specific PRR stimuli they can induce some T cell division, more than B cells or macrophages but typically in the order of 10-fold or less that of the cDC (Villadangos and Young, 2008). Unlike cDC the pDC continually present antigens on MHC class II molecules once they are activated and as a result can continue to present new viral antigens during the course of infection (Young et al., 2008). The importance of this function of pDC during an ongoing infection is not yet elucidated. Instead the pDC, also referred to as natural interferonproducing cells (NIPC), are renowned for their production of Type I interferons (IFN-I) in response to viral or bacterial stimuli and mimics thereof (Gilliet et al., 2008; Kadowaki, 2009). The pDC of both mouse and humans recognize ssDNA via TLR9. As a consequence of endoplasmic reticulum to lysosome internal trafficking of TLR9 and differential expression of molecules that are involved in the TLR9 signaling complex, such as high constitutive expression of IRF7, the pDC have the ability to produce extremely high levels of IFN-I upon TLR9 ligation (Gilliet et al., 2008). Synthetic CpG-containing oligonucleotides (ODN), without addition of transfection reagent, are sufficient for the triggering of IFN-I from pDC. The pDC and a recently identified DC in bone marrow (miDC) (O’Keeffe et al., 2012) are the only cell types known to produce IFN-I in response to CpGODN alone.

Chapter | 12

Dendritic Cells in Autoimmune Disease

DENDRITIC CELLS IN THE MOUSE THYMUS Although thymic DC may serve the same sentinel role as in other tissues, their main role is likely to be in the selection of the specificity repertoire of developing T cells, so ensuring tolerance to self components (Ardavin, 1997). Although thymic epithelial cells are the major source of self antigens for thymocyte selection, DC appear to contribute to negative selection and can collect and present antigens originally produced by the epithelial component (Klein et al., 2011). Thymic DC are of two distinct origins. The CD81 thymic DC are produced endogenously, possibly from the same early precursors that give rise to T cells. They resemble the CD81 conventional DC in peripheral lymphoid organs and, being in the immature state, are likely to induce tolerance. However, their crosspresentation capacity is fully developed and this may be important for presentation of self antigens derived from other thymic cells (Gallegos and Bevan, 2004). In contrast, the thymic CD82 conventional DC appear to be a little more mature than the CD81 thymic DC and they enter the thymus preformed from the bloodstream; this may enable them to carry into the thymus peripheral self antigens for induction of central tolerance. These thymic CD82 DC may also contribute to negative selection, but are particularly effective at generation of regulatory T cells (Proietto et al., 2008). The plasmacytoid cells in the thymus also enter the organ directly from the bloodstream. It is not known whether they play any role in thymic T cell selection, or whether they are simply on patrol in case of a viral infection.

DENDRITIC CELL SUBSETS AND TOLERANCE As discussed above, the CD82 migratory cDC in thymus are particularly efficient in the induction of regulatory T cells (Tregs) in the thymus. This function, together with their ability to carry peripheral tissue antigens into the thymus and to play an important role in the deletion of thymocytes reactive to these self antigens (Bonasio et al., 2006; Proietto et al., 2008) contributes to central tolerance (Proietto et al., 2008). Migratory DC in the gut also play a major role in inducing tolerance, specifically to oral and commensal bacterial antigens. The CD1031 DC in the lamina propria migrate to mesenteric lymph nodes where they produce retinoic acid from dietary vitamin A and induce guthoming Tregs (reviewed in Scott et al., 2011). The CD81 cDC of both spleen and lymph nodes can present self-antigen by endocytosis of apoptotic cells in vivo in the steady state and tolerize self-reactive T cells in the periphery (Iyoda et al., 2002). This ability to cross-

179

present exogenous antigen on MHC class I (den Haan et al., 2000) is probably also responsible for the ability of CD81 cDC to induce peripheral tolerance to tissue associated antigens (Belz et al., 2002). Moreover, CD81 cDC produce TGF-β in the steady state and induce antigenspecific Treg cells, further contributing to peripheral tolerance (Yamazaki et al., 2008). Although the pDC have a remarkable proinflammatory function based on their IFN-I production, they have also been credited with protection from allergy (Lambrecht and Hammad, 2008) and determining oral (Goubier et al., 2008) and transplant tolerance (Abe et al., 2005; Ochando et al., 2006). Mechanisms of tolerance induction and/or immunosuppression by non-activated pDC probably include, but are not limited to, their ability to produce indoleamine-pyrrole 2,3-dioxygenase (IDO, the enzyme catalyzing L-tryptophan to N-formylkynurenine breakdown; Fallarino et al., 2007) and to induce Tregs (Ochando et al., 2006; Hadeiba et al., 2008). DC differentiated from human monocytes or mouse bone marrow in vitro can be rendered tolerogenic by a variety of mechanisms including culture with IL-10 or TGF-β, treatment with drugs such as dexamethasone or BAY 11-7085 that inhibit NF-κB signaling, vitamin D3 or genetic modification by transduction of IL-4, IDO or treatment with antisense oligonucleotides for costimulatory molecules CD80, CD86, and CD40 (Steinman et al., 2003; Thomson and Robbins, 2008; Stoop et al., 2011). Tolerogenic DC differentiated by these mechanisms are characterized by low expression of costimulatory molecules, low production of proinflammatory cytokines, and high production of IL-10. They can induce tolerance by a variety of mechanisms including promotion of T cell death or anergy, the induction of Tregs, diversion of Th1 and Th17 responses towards a Th2 phenotype, and secretion of immunosuppressive molecules such as IDO (Thomson and Robbins, 2008). Vaccination with tolerogenic DC can prevent disease onset and limit disease severity in the collagen-induced arthritis mouse model, a commonly used model of rheumatoid arthritis. Similarly in NOD mice, transfer of tolerogenic DC prevents the onset of diabetes (Giannoukakis et al., 2008; Mukherjee and Dilorenzo, 2010). Several studies have shown a requirement for DC loading with specific autoantigen, e.g., type II collagen for collagen-induced arthritis, or islet beta cell antigens for diabetes, while others have demonstrated better efficacy if DC are not loaded with specific antigen. In the latter case it is presumed that DC acquire autoantigen in vivo. These promising preclinical studies in animal models have provided the impetus for the initiation of a number of Phase I studies in humans using tolerogenic DC as a treatment for rheumatoid arthritis or type 1 diabetes (Thomson and Robbins, 2008). Although the main endpoint of these Phase I trials is safety, results based on defined secondary

180

PART | 3

Non-Antigen-Specific Recognition

TABLE 12.2 Human DC Subsets of Mouse Blood Showing their Expression of C-type Lectins and TLRs and the Mouse DC Subsets to which they Align Human blood DC subsets CD141

CD1c

PDC

MoDC

C-type lectins

Clec9A, DEC-205

DEC-205

CD303 (BDCA2), DEC-205

CD206 (mannose receptor), CD209 (DC-SIGN), DEC-205

Toll-like receptors

TLR3, TLR10

TLR2 (TLR3, 4, 7 weak)

TLR7, TLR9, TLR10

TLR2, TLR4, TLR8

Putative ex vivo Mouse DC counterpart

CD81 DC and CD82Clec9A1 migratory DC subsets

CD82CD11b1 DC subsets

pDC

In vitro generated DC from monocytes with GM-CSF

endpoints are promising in a Phase I rheumatoid arthritis trial, where a decrease in general hyperinflammatory responses was observed in tolerogenic DC-treated patients (Nel et al., 2012) and in a diabetes trial where DC-treated patients showed some evidence of the induction of tolerogenic B cells (Giannoukakis et al., 2011).

HUMAN DENDRITIC CELL SUBSETS IN STEADY STATE The study of human DC subsets is still in its infancy due to their rarity and lack of distinguishing markers and constraints on accessing human tissue. Most human studies have focused on DC differentiated from blood monocytes after in vitro culture in the presence of GM-CSF and IL-4 (MoDC). Their in vivo counterparts are currently unclear, but they most likely resemble the mouse inflammatory DC subtype. Human blood DC comprise approximately 1% of circulating peripheral blood mononuclear cells (PBMC) and are classically defined as Ag-presenting leukocytes that lack other leukocyte lineage markers (CD3, 14, 15, 19, 20, 56) and express high levels of MHC class II (HLA-DR) molecules (lineage2HLA-DR1). Like mouse DC, these can be broadly categorized into pDC (defined as CD11c2CD1231 in humans) and cDC (defined as CD11c1CD1232). Human pDC are functionally aligned with their mouse counterparts and are characterized by expression of TLR7 and TLR9 and their ability to rapidly produce high levels of IFN-I. Conventional DC in human blood comprise the CD141 (BDCA-3)1 and CD1c (BDCA-1)1 DC subsets. These have unique gene expression profiles that are distinct from monocytes and MoDC and this predicts that they have different functions (Lindstedt et al., 2005; Robbins et al., 2008). Human CD1411 DC and mouse CD81 DC share features that are essential for the induction of CTL responses against viruses and tumors (Bachem et al., 2010; Crozat

et al., 2010; Jongbloed et al., 2010; Poulin et al., 2010). They express TLR3 (Edwards et al., 2003; Lindstedt et al., 2005), the C-type lectin Clec9A (Caminschi et al., 2008; Huysamen et al., 2008; Sancho et al., 2008), nectin-like protein 2 (Necl2) (Galibert et al., 2005), and chemokine receptor XCR1 (Bachem et al., 2010; Crozat et al., 2010). Human CD1411 DC and mouse CD81 DC subsets produce IFN-β and IFN-λ in response to poly I:C (Scheu et al., 2008; Jongbloed et al., 2010; Lauterbach et al., 2010) and are specialized in their capacity to cross-present exogenous Ag from necrotic cells on MHC class I for the induction of antiviral and antitumor CD81 T cell responses (den Haan et al., 2000; Iyoda et al., 2002; Schnorrer et al., 2006; Crozat et al., 2010; Jongbloed et al., 2010). However, a key difference is that TLR9 is expressed by mouse CD81 DC but not by human CD1411 DC and this would predict interspecies differences in the capacity of DC to respond to ssDNA. The function of the human CD1c1 DC subset, and whether it aligns with the mouse CD11b1CD82 DC subset as predicted by their transcriptomes, has not been defined. Human CD1c1 DC and CD1411 DC are also found in lymph nodes, tonsil, spleen, skin, liver, gut, and lung. Table 12.2 shows human DC subsets, aligned with putative mouse equivalents.

DENDRITIC CELL SUBSETS IN HUMAN SKIN: EPIDERMAL LANGERHANS CELLS AND DERMAL DENDRITIC CELLS Langerhans cells (LCs) are the main DC subset located in the epidermis of human skin. LCs are considered as the classical sentinels that are at the forefront of contact with invading microbial pathogens in the epidermis. They are characterized by expression of langerin (CD207) that functions as a receptor for microbial pathogens, and E-cadherin which facilitates adhesion with nearby keratinocytes (Cunningham et al., 2010). Human LCs are powerful stimulators of CD41 T cell proliferation and induce

Chapter | 12

Dendritic Cells in Autoimmune Disease

polarization towards a Th2 phenotype characterized by production of IL-4, IL-5, and IL-13 (Klechevsky et al., 2008). Human LCs can cross-present antigens and are potent stimulators of naı¨ve CD81 T cell whereas most studies in mice do not support a role for LC in crosspresentation and the induction of antiviral CD81 T cell responses. Although LCs have been implicated in the inhibition of inflammation and the induction of tolerance in mice, these functions are yet to be addressed in humans. Three separate populations of DC have been found in human dermis (Klechevsky et al., 2008; Nestle et al., 2009; Zaba et al., 2009; Haniffa et al., 2012). The first subset of dermal DC can be defined by expression of CD14. These DC play a specialized role in the development of humoral B cell responses by promoting the differentiation of CD41 T cells into follicular Th cells that prime naı¨ve B cells to become plasma cells (Klechevsky et al., 2008). A subpopulation of CD141 dermal DC constitutively expresses IL-10 and induces Tregs that inhibit skin inflammation (Chu et al., 2012). The CD142 dermal DC can be further subdivided into two populations based on reciprocally high expression of CD141 or CD1c. Like human blood CD1411 DC and the mouse lymphoid resident CD81 and migratory CD1031 DC, human dermal CD141hi DC share expression of TLR3, Clec9A, XCR1, Necl2, and are superior to other dermal DC and epidermal LC in their capacity to cross-present Ag to CD81 T cells (Haniffa et al., 2012). pDC are rare in healthy human skin but accumulate in inflamed tissue and facilitate disease pathogenesis in systemic lupus erythematosus (SLE) and psoriasis (Blanco et al., 2001; Nestle et al., 2005). Inflammatory myeloid DC infiltrate both epidermis and dermis of psoriatic lesions and are proposed to play a major role in psoriasis pathogenesis by production of the inflammatory mediators, inducible nitric oxide synthase (iNOS), and TNF-α (Lowes et al., 2005; Zaba et al., 2009).

DENDRITIC CELLS AND AUTOIMMUNE DISEASE The DC subsets show a remarkable dichotomy in function relating to the induction of thymic and peripheral tolerance, as well as the induction of potent inflammatory responses to activation stimuli. Many factors, still mostly unknown, must control this finely tuned balance. Likewise, many factors contribute to autoimmune disease but clearly an imbalance in the tolerizing versus activation states of DC would lead to or enhance autoimmune disease. Two examples of this are discussed below.

Systemic Lupus Erythematosus B cells and T cells in SLE are autoreactive to self nucleic acids (dsDNA, ssDNA, and RNA) and nuclear proteins,

181

particularly nuclear antigens, including RNA-binding proteins such as those associated with U1-RNA (Migliorini et al., 2005). The exact mechanisms that drive development and activation of these autoreactive lymphocytes in SLE remain unknown but genetic influences play a major role in determining susceptibility (see Chapter 26). HLA loci have been linked to SLE, as have more than 30 additional genes, including many involved in proinflammatory cascades, e.g., genes encoding Fcγ receptors, TNFSF4, IRAK1, STAT4 (Delgado-Vega et al., 2010; Deng and Tsao, 2010; Sestak et al., 2011). Many of these genes are involved in pathways leading to production of type I interferons (IFN-I) or responses to IFN-I (Deng and Tsao, 2010). Indeed many patients with SLE typically carry an “IFN signature” (Ro¨nnblom and Pascual, 2008) as evidence of the expression of genes that are dependent on IFN-I for transcription. IFN-I in SLE is predominantly produced by pDC that respond to nucleic acid/autoantibody complexes via signaling through TLR7 and TLR9 (Means et al., 2005; Ro¨nnblom and Pascual, 2008). Delivery of nucleic acid complexes to pDC in SLE depends on FcR that bind antinucleic acid immune complexes (Means et al., 2005) or nucleic acid complexes associated with neutrophils. Dying neutrophils in SLE patients release neutrophil extracellular traps (NETs); these neutrophils die from “netosis,” thereby releasing large amounts of DNA/DNA-binding antimicrobial protein complexes that allow increased uptake of DNA by pDC and subsequent IFN-I production by TLR9-induced activation (Garcia-Romo et al., 2011; see Chapter 11). IFN-I production in SLE is seen as a major contributor to the etiology of this disease since it greatly enhances activation of DC, self-reactive B cells and T cells, and the production of many other proinflammatory cytokines. Although studies of IFN-I in SLE suggest this as a therapeutic target, it is important to recognize that the same IFN signature can be induced by another family of IFNs produced by pDC, the type III IFNs, also called IFNlambda (IFN-λ). As for type I IFNs (particularly IFN-α), pDC are a major source of IFN-λ in response to TLR9 signaling in mice, and to both TLR7 and 9 in humans; pDC also produce large amounts of IFN-λ in response to viral stimulation (Ank and Paludan, 2009). Apart from pDC, the human CD1411 DC and mouse CD81 DC also produce large amounts of IFN-λ in response to dsRNA via TLR3. Our unpublished data indicate that, similarly to IFN-I, IFN-λ enhances DC activation and it is thus very likely that IFN-λ production by DC subsets, like IFN-α, will play a role in enhancing proinflammatory responses in autoimmune diseases like SLE and also psoriasis where self nucleic acids are major immunogens.

182

IBD—Crohn’s Disease and Ulcerative Colitis Inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CrD) are not initiated by an endogenous autoimmune event, but the pathology is autoimmune in nature. These diseases are presumed to manifest as a result of dysregulated immune responses to the intestinal microbiota. Mutations in NLR family members NOD2 and NLRP3 are highly associated with CrD (Cho, 2008; Villani et al., 2009). These PRR are mainly expressed by DC and macrophages and emerging evidence suggests they play a crucial role in maintaining immunological homeostasis in the intestine (Strober et al., 2006; Zaki et al., 2011). NOD2 functions as a receptor for the bacterial cell wall component muramyl dipeptide (MDP). Triggering of NOD2 in human MoDC in vitro stimulates processing and presentation of bacterial antigens to CD41 T cells, so generating an antibacterial response due to an increased production of antibacterial IL-17 (Cooney et al., 2010; van Beelen et al., 2007). NLRP3 is activated by a wide variety of microbial agonists and drives IL-1β secretion that activates the antimicrobial functions of innate immune cells such as macrophages and DC, and induces CD41 Th17 immune responses (Schroder et al., 2010). Thus, abnormal signaling by DC in response to the intestinal microbiota, consequent to mutations in these PRR, likely contributes to the pathogenesis of CrD. Further evidence derived from mice and humans suggests that an imbalance in intestinal DC subsets, distribution, and function plays a crucial role driving inflammation and disease pathogenesis (Ng et al., 2011; Varol et al., 2010). Depletion of DC in mouse models of colitis leads to increased or decreased disease severity depending on the time-point, demonstrating a crucial role for DC in both the downregulation and exacerbation of intestinal inflammation. The balance between the functions of mouse intestinal CD1031 and CX3CR11 DC subsets regulates immune homeostasis and controls inflammatory responses. CD1031 DC are migratory DC that reside in the lamina propria and transport microbial antigens to the lymph nodes where they play an essential role in the induction of peripheral Tregs and the generation of oral tolerance. In contrast, the levels of CX3CR11 DC are dramatically increased in mouse colitis models and augment the severity of disease. pDC also accumulate in intestinal tissue in mouse colitis models (Karlis et al., 2004) and are contributors to the protective effects of GM-CSF treatment on colitis (Sainathan et al., 2008). DC (defined as lacking the markers of other cell lineages and having high levels of MHC class II) can be found in the lamina propria of the human colonic mucosa (Ng et al., 2010). They comprise mostly CD11c1 cDC

PART | 3

Non-Antigen-Specific Recognition

and few pDC, but their phenotype, function, and degree of alignment with mouse DC subsets is poorly characterized. Increased numbers of activated cDC are found in inflamed tissue in CrD compared to non-inflamed tissue, supporting a role for DC in disease pathogenesis (Ng et al., 2011). These DC express CD40 and CD83, TLR2 and TLR4, and produce proinflammatory cytokines including IL-6, TNF, and IL-12. An increased number of pDC are also present in the colonic mucosa and mesenteric lymph nodes of patients with CrD and ulcerative colitis (Baumgart et al., 2011). However, pDC infiltration in the lamina propria is associated with a clinical response and remission in patients with CrD following G-CSF treatment (Mannon et al., 2009). Thus the contribution of pDC to IBD pathogenesis remains unclear.

DENDRITIC CELL IMMUNOTHERAPY AS A TREATMENT FOR AUTOIMMUNE DISEASES The essential role of DC in inducing immune responses makes them attractive targets for the development of immunomodulatory vaccines. DC loaded ex vivo with antigen and activators and administered as vaccines have been used as a treatment for a variety of malignancies (Vulink et al., 2008; Palucka and Banchereau, 2012) and some infectious diseases (Garcı´a and Routy, 2011). These studies have demonstrated that DC vaccination is safe and to a degree efficacious. While vaccination with activated DC induces proinflammatory B cell and T cell adaptive immune responses, vaccination with immature DC results in the expansion of IL-10-secreting, Tregs (Dhodapkar et al., 2001). These studies provide some rationale for the adaptation of DC immunotherapy to induce a tolerogenic immune response for the treatment of autoimmune diseases.

TARGETING OF DENDRITIC CELLS IN AUTOIMMUNE DISEASE Ex vivo manipulation of DC is expensive, logistically impractical, complicated by regulations, and needs to be tailored specifically for individual patients. Delivering antigen to DC directly in vivo using antibodies specific for DC-associated molecules such as DEC-205 can overcome many of the current limitations of DC therapy (Tacken et al., 2007). This approach is currently in early phase clinical trials for cancer and is just beginning to be explored in preclinical experimental models for autoimmune diseases. In the absence of adjuvant, targeting antigen to DC in vivo using antibodies to DEC205 induces antigen-specific T cell deletion and unresponsiveness to oligodendrocyte glycoprotein (MOG) in a model of autoimmune experimental acute

Chapter | 12

Dendritic Cells in Autoimmune Disease

encephalomyelitis and to model antigens including ovalbumin (Bonifaz et al., 2002; Hawiger et al., 2004). Furthermore, DEC-205 targeting of autoantigens in the NOD and other mouse models of type 1 diabetes prevents disease onset and progression (Bruder et al., 2005; Mukhopadhaya et al., 2008). An alternative approach being developed is microspheres carrying CD40, CD80, and CD86 antisense oligonucleotides. Vaccination with these microspheres can prevent and reverse new-onset type 1 diabetes in NOD mice, presumably via uptake by DC in vivo and the expansion of Tregs (Phillips et al., 2008). Targeting the innate functions of DC, such as cytokine production, is also likely to be successful in autoimmune diseases that are known to have a detrimental DC functional component. The example of SLE cited above is a key candidate for pDC targeting. Targeting strategies that block TLR7 and 9, for example, would extinguish the IFN-I production by pDC in response to self-nucleic acids in SLE.

CONCLUSIONS AND FUTURE PROSPECTS The roles of DC subsets in mice, and mouse models of disease, are steadily being deciphered. The field has really only just begun to understand the complexity of function of different DC subsets in humans and how they may contribute to disease. Unraveling the functions of DC subsets in different anatomical locations will continue to lend insight into their potential roles in disease states. There is a real possibility that directly targeting DC either through harnessing or dampening their specific functions may lead to novel tailored therapies for autoimmune diseases. It will be a great challenge to induce tolerogenic DC in humans. DC will be targeted with antibodies to specific surface receptors that are directly conjugated either to drugs or to the surface of nanocomplexes. As described above, drugs such as those that inhibit NF-κB signaling can freeze DC in a tolerogenic state. Drugs that inhibit TLR-7 or 9 signaling would prevent pDC activation in SLE. The combination of antibody, drug, and antigen, delivered in a nanocomplex, will perhaps ultimately create the perfect tolerogenic, DC-targeting vaccine. The challenge is to determine what is the best antibody, the best anti-inflammatory drug, the best antigen, and how best to complex these in a nanoparticle-like delivery system, for different types of autoimmune disease. In addition, DC may be increased in vivo using growth factors, such as Flt-3 ligand, that we know are safe and induce high numbers of DC (Maraskovsky et al., 2000). These DC would then be targeted by a tolerizing vaccine. Large numbers of tolerogenic DC may be extremely efficient at maintaining a tolerogenic state. The challenge here would be in the timing, since any increase in DC

183

that are amenable to activation in an inflammatory state would presumably only exacerbate disease.

REFERENCES Abe, M., Wang, Z., de Creus, A., Thomson, A.W., 2005. Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am. J. Transplant. 5, 1808 1819. Ank, N., Paludan, S.R., 2009. Type III IFNs: new layers of complexity in innate antiviral immunity. Biofactors. 35, 82 87. Ardavin, C., 1997. Thymic dendritic cells. Immunol Today. 18, 350 361. Bachem, A., Guttler, S., Hartung, E., Ebstein, F., Schaefer, M., Tannert, A., et al., 2010. Superior antigen cross-presentation and XCR1 expression define human CD11c1 CD1411 cells as homologues of mouse CD81 dendritic cells. J. Exp. Med. 207, 1273 1281. Banchereau, J., Steinman, R.M., 1998. Dendritic cells and the control of immunity. Nature. 392, 245 252. Barbalat, R., Ewald, S.E., Mouchess, M.L., Barton, G.M., 2011. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185 214. Baumgart, D.C., Metzke, D., Guckelberger, O., Pascher, A., Grotzinger, C., Przesdzing, I., et al., 2011. Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn’s disease and ulcerative colitis. Clin. Exp. Immunol. 166, 46 54. Belz, G.T., Behrens, G.M., Smith, C.M., Miller, J.F., Jones, C., Lejon, K., et al., 2002. The CD8alpha(1) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J. Exp. Med. 196, 1099 1104. Blanco, P., Palucka, A.K., Gill, M., Pascual, V., Banchereau, J., 2001. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 294, 1540 1543. Bonasio, R., Scimone, M.L., Schaerli, P., Grabie, N., Lichtman, A.H., von Andrian, U.H., 2006. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7, 1092 1100. Bonifaz, L., Bonnyay, D., Mahnke, K., Rivera, M., Nussenzweig, M.C., Steinman, R.M., 2002. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD81 T cell tolerance. J. Exp. Med. 196, 1627 1638. Bruder, D., Westendorf, A.M., Hansen, W., Prettin, S., Gruber, A.D., Qian, Y., et al., 2005. On the edge of autoimmunity: T-cell stimulation by steady-state dendritic cells prevents autoimmune diabetes. Diabetes. 54, 3395 3401. Bursch, L.S., Wang, L., Igyarto, B., Kissenpfennig, A., Malissen, B., Kaplan, D.H., et al., 2007. Identification of a novel population of Langerin 1 dendritic cells. J. Exp. Med. 204, 3147 3156. Caminschi, I., Proietto, A.I., Ahmet, F., Kitsoulis, S., Shin Teh, J., Lo, J.C., et al., 2008. The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood. 112, 3264 3273. Cho, J.H., 2008. The genetics and immunopathogenesis of inflammatory bowel disease. Nat. Rev. Immunol. 8, 458 466. Chu, C.C., Ali, N., Karagiannis, P., Di Meglio, P., Skowera, A., Napolitano, L., et al., 2012. Resident CD141 (BDCA3) 1 dendritic

184

cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation. J. Exp. Med. 209, 935 945. Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., et al., 2010. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16, 90 97. Crozat, K., Guiton, R., Contreras, V., Feuillet, V., Dutertre, C.A., Ventre, E., et al., 2010. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha 1 dendritic cells. J. Exp. Med. 207, 1283 1292. Cunningham, A.L., Abendroth, A., Jones, C., Nasr, N., Turville, S., 2010. Viruses and Langerhans cells. Immunol. Cell Biol. 88, 416 423. Davis, B.K., Wen, H., Ting, J.P.Y., 2011. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29, 707 735. Delgado-Vega, A., Sanchez, E., Lofgren, S., Castillejo-Lopez, C., Alarcon-Riquelme, M.E., 2010. Recent findings on genetics of systemic autoimmune diseases. Curr. Opin. Immunol. 22, 698 705. den Haan, J.M., Lehar, S.M., Bevan, M.J., 2000. CD8(1) but not CD8 (2) dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192, 1685 1696. Deng, Y., Tsao, B.P., 2010. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat. Rev. Rheumatol. 6, 683 692. Dhodapkar, M.V., Steinman, R.M., Krasovsky, J., Munz, C., Bhardwaj, N., 2001. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233 238. Diebold, S.S., 2009. Activation of dendritic cells by toll-like receptors and C-type lectins. Handb. Exp. Pharmacol. 3 30. Edwards, A.D., Chaussabel, D., Tomlinson, S., Schulz, O., Sher, A., Reis e Sousa, C., 2003. Relationships among murine CD11c(high) dendritic cell subsets as revealed by baseline gene expression patterns. J. Immunol. 171, 47 60. Elinav, E., Strowig, T., Henao-Mejia, J., Flavell, Richard, A., 2011. Regulation of the Antimicrobial Response by NLR Proteins. Immunity 34, 665 679. Fallarino, F., Gizzi, S., Mosci, P., Grohmann, U., Puccetti, P., 2007. Tryptophan catabolism in IDO 1 plasmacytoid dendritic cells. Curr. Drug Metab. 8, 209 216. Galibert, L., Diemer, G.S., Liu, Z., Johnson, R.S., Smith, J.L., Walzer, T., et al., 2005. Nectin-like protein 2 defines a subset of T-cell zone dendritic cells and is a ligand for class-I-restricted T-cell-associated molecule. J. Biol. Chem. 280, 21955 21964. Gallegos, A.M., Bevan, M.J., 2004. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039 1049. Garcia-Romo, G.S., Caielli, S., Vega, B., Connolly, J., Allantaz, F., Xu, Z., et al., 2011. Netting neutrophils are major inducers of type i ifn production in pediatric systemic lupus erythematosus. Sci. Translational Med. 3, 73ra20. Garcı´a, F., Routy, J.-P., 2011. Challenges in dendritic cells-based therapeutic vaccination in HIV-1 infection: Workshop in dendritic cellbased vaccine clinical trials in HIV-1. Vaccine 29, 6454 6463. Giannoukakis, N., Phillips, B., Finegold, D., Harnaha, J., Trucco, M., 2011. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care 34, 2026 2032.

PART | 3

Non-Antigen-Specific Recognition

Giannoukakis, N., Phillips, B., Trucco, M., 2008. Toward a cure for type 1 diabetes mellitus: diabetes-suppressive dendritic cells and beyond. Pediatr. Diabetes 9, 4 13. Gilliet, M., Cao, W., Liu, Y.J., 2008. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat. Rev. Immunol. 8, 594 606. Goubier, A., Dubois, B., Gheit, H., Joubert, G., Villard-Truc, F., Asselin-Paturel, C., et al., 2008. Plasmacytoid dendritic cells mediate oral tolerance. Immunity 29, 464 475. Greter, M., Helft, J., Chow, A., Hashimoto, D., Mortha, A., AgudoCantero, J., et al., 2012. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity. 36, 1031 1046. Hadeiba, H., Sato, T., Habtezion, A., Oderup, C., Pan, J., Butcher, E.C., 2008. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat. Immunol. 9, 1253 1260. Haniffa, M., Shin, A., Bigley, V., McGovern, N., Teo, P., See, P., et al., 2012. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103 1 nonlymphoid dendritic cells. Immunity 37, 60 73. Hawiger, D., Masilamani, R.F., Bettelli, E., Kuchroo, V.K., Nussenzweig, M.C., 2004. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity. 20, 695 705. Heath, W.R., Belz, G.T., Behrens, G.M., Smith, C.M., Forehan, S.P., Parish, I.A., et al., 2004. Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol. Rev. 199, 9 26. Hochrein, H., O’Keeffe, M., 2008. Dendritic cell subsets and toll-like receptors. Handb. Exp. Pharmacol.153 179. Hochrein, H., Shortman, K., Vremec, D., Scott, B., Hertzog, P., O’Keeffe, M., 2001. Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets. J. Immunol. 166, 5448 5455. Huysamen, C., Willment, J.A., Dennehy, K.M., Brown, G.D., 2008. CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3 1 dendritic cells and a subset of monocytes. J. Biol. Chem. 283, 16693 16701. Iyoda, T., Shimoyama, S., Liu, K., Omatsu, Y., Akiyama, Y., Maeda, Y., et al., 2002. The CD8 1 dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J. Exp. Med. 195, 1289 1302. Jongbloed, S.L., Kassianos, A.J., McDonald, K.J., Clark, G.J., Ju, X., Angel, C.E., et al., 2010. Human CD141 1 (BDCA-3) 1 dendritic cells (DCs) represent a unique myeloid DC subset that crosspresents necrotic cell antigens. J. Exp. Med. 207, 1247 1260. Kadowaki, N., 2009. The divergence and interplay between pDC and mDC in humans. Front Biosci. 14, 808 817. Karlis, J., Penttila, I., Tran, T.B., Jones, B., Nobbs, S., Zola, H., et al., 2004. Characterization of colonic and mesenteric lymph node dendritic cell subpopulations in a murine adoptive transfer model of inflammatory bowel disease. Inflamm. Bowel. Dis. 10, 834 847. Kasahara, S., Clark, E.A., 2012. Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8alpha- dendritic cell subset. J. Leukoc. Biol. 91, 437 448. Kawai, T., Akira, S., 2007. Antiviral signaling through pattern recognition receptors. J. Biochem. 141, 137 145.

Chapter | 12

Dendritic Cells in Autoimmune Disease

Kawai, T., Akira, S., 2010. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373 384. Kawai, T., Akira, S., 2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637 650. Kerrigan, A.M., Brown, G.D., 2009. C-type lectins and phagocytosis. Immunobiology. 182, 4150 4157. Klechevsky, E., Morita, R., Liu, M., Cao, Y., Coquery, S., ThompsonSnipes, L., et al., 2008. Functional specializations of human epidermal Langerhans cells and CD14 1 dermal dendritic cells. Immunity 29, 497 510. Klein, L., Hinterberger, M., von Rohrscheidt, J., Aichinger, M., 2011. Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol. 32, 188 193. Lambrecht, B.N., Hammad, H., 2008. Lung dendritic cells: targets for therapy in allergic disease. Chem. Immunol. Allergy 94, 189 200. Lauterbach, H., Bathke, B., Gilles, S., Traidl-Hoffmann, C., Luber, C.A., Fejer, G., et al., 2010. Mouse CD8α 1 DCs and human BDCA3 1 DCs are major producers of IFN-λ in response to poly IC. J. Exp. Med. 207, 2703 2717. Lindstedt, M., Lundberg, K., Borrebaeck, C.A., 2005. Gene family clustering identifies functionally associated subsets of human in vivo blood and tonsillar dendritic cells. J. Immunol. 175, 4839 4846. Loo, Y.-M., Gale Jr., M., 2011. Immune signaling by RIG-I-like receptors. Immunity 34, 680 692. Lowes, M.A., Chamian, F., Abello, M.V., Fuentes-Duculan, J., Lin, S.L., Nussbaum, R., et al., 2005. Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc. Natl. Acad. Sci. USA 102, 19057 19062. Luber, C.A., Cox, J., Lauterbach, H., Fancke, B., Selbach, M., Tschopp, J., et al., 2010. Quantitative proteomics reveals subset-specific viral recognition in dendritic cells. Immunity 32, 279 289. Maldonado-Lopez, R., De Smedt, T., Michel, P., Godfroid, J., Pajak, B., Heirman, C., et al., 1999. CD8alpha 1 and CD8alpha 2 subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189, 587 592. Mannon, P.J., Leon, F., Fuss, I.J., Walter, B.A., Begnami, M., Quezado, M., et al., 2009. Successful granulocyte-colony stimulating factor treatment of Crohn’s disease is associated with the appearance of circulating interleukin-10-producing T cells and increased lamina propria plasmacytoid dendritic cells. Clin. Exp. Immunol. 155, 447 456. Maraskovsky, E., Daro, E., Roux, E., Teepe, M., Maliszewski, C.R., Hoek, J., et al., 2000. In vivo generation of human dendritic cell subsets by Flt3 ligand. Blood 96, 878 884. Martinon, F., Tschopp, J., 2005. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447 454. Means, T.K., Latz, E., Hayashi, F., Murali, M.R., Golenbock, D.T., Luster, A.D., 2005. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407 417. Merad, M., Ginhoux, F., Collin, M., 2008. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat. Rev. Immunol. 8, 935 947.

185

Migliorini, P., Baldini, C., Rocchi, V., Bombardieri, S., 2005. Anti-Sm and anti-RNP antibodies. Autoimmunity 38, 47 54. Mukherjee, G., Dilorenzo, T.P., 2010. The immunotherapeutic potential of dendritic cells in type 1 diabetes. Clin. Exp. Immunol. 161, 197 207. Mukhopadhaya, A., Hanafusa, T., Jarchum, I., Chen, Y.G., Iwai, Y., Serreze, D.V., et al., 2008. Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8 1 T cells in NOD mice. Proc. Natl. Acad. Sci. USA 105, 6374 6379. Nagao, K., Ginhoux, F., Leitner, W.W., Motegi, S., Bennett, C.L., Clausen, B.E., et al., 2009. Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions. Proc. Natl. Acad. Sci. U. S. A. 106, 3312 3317. Nel, H., Law, S., Street, S., Ramnoruth, N., Shams, R., Pahau, H., et al., 2012. ARA scientific posters, ARA-P6. Outcome of a phase I trial of Rheumavax in patients with rheumatoid arthritis. Internal Med. J. 42, 9 35. Nestle, F.O., Conrad, C., Tun-Kyi, A., Homey, B., Gombert, M., Boyman, O., et al., 2005. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135 143. Nestle, F.O., Di Meglio, P., Qin, J.Z., Nickoloff, B.J., 2009. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679 691. Ng, S.C., Kamm, M.A., Stagg, A.J., Knight, S.C., 2010. Intestinal dendritic cells: their role in bacterial recognition, lymphocyte homing, and intestinal inflammation. Inflamm. Bowel Dis. 16, 1787 1807. Ng, S.C., Benjamin, J.L., McCarthy, N.E., Hedin, C.R., Koutsoumpas, A., Plamondon, S., et al., 2011. Relationship between human intestinal dendritic cells, gut microbiota, and disease activity in Crohn’s disease. Inflamm. Bowel Dis. 17, 2027 2037. O’Keeffe, M., Fancke, B., Suter, M., Ramm, G., Clark, J., Wu, L., et al., 2012. Nonplasmacytoid, high IFN-alpha-producing, bone marrow dendritic cells. J. Immunol. 188, 3774 3783. O’Keeffe, M., Hochrein, H., Vremec, D., Caminschi, I., Miller, J.L., Anders, E.M., et al., 2002. Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8(1) dendritic cells only after microbial stimulus. J. Exp. Med. 196, 1307 1319. Ochando, J.C., Homma, C., Yang, Y., Hidalgo, A., Garin, A., Tacke, F., et al., 2006. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 7, 652 662. Osorio, F., Reis e Sousa, C., 2011. Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity 34, 651 664. Palucka, K., Banchereau, J., 2012. Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer 12, 265 277. Phillips, B., Nylander, K., Harnaha, J., Machen, J., Lakomy, R., Styche, A., et al., 2008. A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes. Diabetes 57, 1544 1555. Poulin, L.F., Henri, S., de Bovis, B., Devilard, E., Kissenpfennig, A., Malissen, B., 2007. The dermis contains langerin 1 dendritic cells that develop and function independently of epidermal Langerhans cells. J. Exp. Med. 204, 3119 3131. Poulin, L.F., Salio, M., Griessinger, E., Anjos-Afonso, F., Craciun, L., Chen, J.L., et al., 2010. Characterization of human DNGR-1 1 BDCA3 1 leukocytes as putative equivalents of mouse CD8alpha 1 dendritic cells. J. Exp. Med. 207, 1261 1271.

186

Proietto, A.I., O’Keeffe, M., Gartlan, K., Wright, M.D., Shortman, K., Wu, L., et al., 2004. Differential production of inflammatory chemokines by murine dendritic cell subsets. Immunobiology 209, 163 172. Proietto, A.I., van Dommelen, S., Zhou, P., Rizzitelli, A., D’Amico, A., Steptoe, R.J., et al., 2008. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl. Acad. Sci. USA 105, 19869 19874. Reis e Sousa, C., Hieny, S., Scharton-Kersten, T., Jankovic, D., Charest, H., Germain, R.N., et al., 1997. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med. 186, 1819 1829. Robbins, S.H., Walzer, T., Dembele, D., Thibault, C., Defays, A., Bessou, G., et al., 2008. Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol. 9, R17. Robinson, M.J., Sancho, D., Slack, E.C., LeibundGut-Landmann, S., Reis e Sousa, C., 2006. Myeloid C-type lectins in innate immunity. Nat. Immunol. 7, 1258 1265. Ro¨nnblom, L., Pascual, V., 2008. The innate immune system in SLE: type I interferons and dendritic cells. Lupus. 17, 394 399. Sainathan, S.K., Hanna, E.M., Gong, Q., Bishnupuri, K.S., Luo, Q., Colonna, M., et al., 2008. Granulocyte macrophage colonystimulating factor ameliorates DSS-induced experimental colitis. Inflamm. Bowel Dis. 14, 88 99. Sancho, D., Joffre, O.P., Keller, A.M., Rogers, N.C., Martinez, D., HernanzFalcon, P., et al., 2009. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899 903. Sancho, D., Mourao-Sa, D., Joffre, O.P., Schulz, O., Rogers, N.C., Pennington, D.J., et al., 2008. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J. Clin. Invest. 118, 2098 2110. Scheu, S., Dresing, P., Locksley, R.M., 2008. Visualization of IFNbeta production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo. Proc. Natl. Acad. Sci. USA 105, 20416 20421. Schnorrer, P., Behrens, G.M., Wilson, N.S., Pooley, J.L., Smith, C.M., El-Sukkari, D., et al., 2006. The dominant role of CD8 1 dendritic cells in cross-presentation is not dictated by antigen capture. Proc. Natl. Acad. Sci. USA 103, 10729 10734. Schroder, K., Zhou, R., Tschopp, J., 2010. The NLRP3 inflammasome: a sensor for metabolic danger? Science. 327, 296 300. Scott, C.L., Aumeunier, A.M., Mowat, A.M., 2011. Intestinal CD103 1 dendritic cells: master regulators of tolerance? Trends in Immunol. 32, 412 419. Sestak, A.L., Furnrohr, B.G., Harley, J.B., Merrill, J.T., Namjou, B., 2011. The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann. Rheum. Dis. 70 (Suppl. 1), i37 i43. Shklovskaya, E., O’Sullivan, B.J., Ng, L.G., Roediger, B., Thomas, R., Weninger, W., et al., 2011. Langerhans cells are precommitted to immune tolerance induction. Proc. Natl. Acad. Sci. USA 108, 18049 18054. Shortman, K., Heath, W.R., 2010. The CD8 1 dendritic cell subset. Immunol. Rev. 234, 18 31. Steinman, R.M., Cohn, Z.A., 1973. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J. Exp. Med. 137, 1142 1162.

PART | 3

Non-Antigen-Specific Recognition

Steinman, R.M., Hawiger, D., Nussenzweig, M.C., 2003. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685 711. Stoop, J.N., Robinson, J.H., Hilkens, C.M., 2011. Developing tolerogenic dendritic cell therapy for rheumatoid arthritis: what can we learn from mouse models? Ann. Rheum. Dis. 70, 1526 1533. Strober, W., Murray, P.J., Kitani, A., Watanabe, T., 2006. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat. Rev. Immunol. 6, 9 20. Tacken, P.J., de Vries, I.J., Torensma, R., Figdor, C.G., 2007. Dendriticcell immunotherapy: from ex vivo loading to in vivo targeting. Nat. Rev. Immunol. 7, 790 802. Thomson, A.W., Robbins, P.D., 2008. Tolerogenic dendritic cells for autoimmune disease and transplantation. Ann. Rheum. Dis. 67 (Suppl. 3), iii90 iii96. Trombetta, E.S., Mellman, I., 2005. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975 1028. Uematsu, S., Akira, S., 2008. Toll-Like receptors (TLRs) and their ligands 8. Handb. Exp. Pharmacol. 1 20. van Beelen, A.J., Zelinkova, Z., Taanman-Kueter, E.W., Muller, F.J., Hommes, D.W., Zaat, S.A., et al., 2007. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27, 660 669. Varol, C., Zigmond, E., Jung, S., 2010. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nat. Rev. Immunol. 10, 415 426. Villadangos, J.A., Schnorrer, P., 2007. Intrinsic and cooperative antigenpresenting functions of dendritic-cell subsets in vivo. Nat. Rev. Immunol. 7, 543 555. Villadangos, J.A., Young, L., 2008. Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29, 352 361. Villani, A.C., Lemire, M., Fortin, G., Louis, E., Silverberg, M.S., Collette, C., et al., 2009. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat Genet. 41, 71 76. Vulink, A., Radford, K.J., Melief, C., Hart, D.N., 2008. Dendritic cells in cancer immunotherapy. Adv. Cancer Res. 99, 363 407. Wilson, N.S., Villadangos, J.A., 2005. Regulation of antigen presentation and cross-presentation in the dendritic cell network: facts, hypothesis, and immunological implications. Adv. Immunol. 86, 241 305. Yamazaki, S., Dudziak, D., Heidkamp, G.F., Fiorese, C., Bonito, A.J., Inaba, K., et al., 2008. CD8 1 CD205 1 splenic dendritic cells are specialized to induce Foxp3 1 regulatory T cells. J. Immunol. 181, 6923 6933. Young, L.J., Wilson, N.S., Schnorrer, P., Proietto, A., ten Broeke, T., Matsuki, Y., et al., 2008. Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat. Immunol. 9, 1244 1252. Zaba, L.C., Krueger, J.G., Lowes, M.A., 2009. Resident and “inflammatory” dendritic cells in human skin. J. Invest. Dermatol. 129, 302 308. Zaki, M.H., Lamkanfi, M., Kanneganti, T.D., 2011. The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends Immunol. 32, 171 179. Zhang, J.G., Czabotar, P.E., Policheni, A.N., Caminschi, I., Wan, S.S., Kitsoulis, S., et al., 2012. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity 36, 646 657.