DC lineage and subsets
From skin dendritic cells to a simplified classification of human and mouse dendritic
cell subsets
Martin Guilliams1,2,3, Sandrine Henri1,2,3, Samira Tamoutounour1,2,3, Laurence Ardouin1,2,3, Isabelle Schwartz-Cornil4, Marc Dalod1,2,3and Bernard Malissen1,2,3
1
Centre d’Immunologie de Marseille-Luminy, Universite´ de la Me´diterrane´e, Marseille Cedex 9, France
2
INSERM, U631, Marseille Cedex 9, France 3
CNRS, UMR6102, Marseille Cedex 9, France 4
Virologie et Immunologie Mole´culaires, UR892 INRA, Jouy-en-Josas, France DOI 10.1002/eji.201040498
Recent studies have identified several DC subsets within the mouse skin and showed that functional specialization exists among them. This Viewpoint
summarizes recent data on functional specialization of skin DC subsets and integrates this knowledge into a unifying DC classification that emphasizes the similarities between the DC subsets found in both lymphoid and non-lymphoid tissues of several mammalian species.
Unraveling the complexity of the skin DC network
Epidermal Langerhans cells (LC) have long been regarded as the exclusive DC of the skin, taking up pathogens or allergens that penetrate the epidermis. After switching from a sessile to a mobile state, LC carry these antigens to the LN that drain cutaneous terri-tories (CLN) [1]. Recent studies, however, demonstrated the existence of a complex network of dermal DC (DDC) and also suggested that LC might play an indirect role in T-cell priming, i.e. by ferrying antigens to those DC that reside throughout their life cycle in the CLN [2]. These ‘‘resident’’ DC are generally denoted as lymphoid tissue-resident DC (LT-DC) to distinguish them from non-lymphoid tissue-derived, migratory DC (mig-DC), such as LC.
Based on the assumption that the C-type lectin CD207 (Langerin) is specifically expressed in LC, knock-in
mice expressing a green fluorescent protein under the control of theCd207 gene were engineered to distinguish LC from other DC subsets; however, the CD207-knock-in mice revealed that the CD8aLT-DC present in LN and spleens of some mouse strains also express CD207, albeit at lower levels than LC [3, 4]. Moreover, using knock-in mice in which CD2071 DC were rendered sensitive to diphtheria toxin [5], a major fraction of the skin-derived CD2071 DC present in the CLN was found to develop independently of epidermal LC [6–9]. Therefore, the expression of CD207 is more complex than originally thought and allows the identification of three DC subsets corresponding to LC, CD2071 DDC and CD8a1CD207lowDC. By combining the expression of CD207, CD11b and CD103, five distinct DC subsets have been further identified in steady-state (non-inflammatory) dermis [10]. CD207–CD11b1 DDC represent the major DDC subset, whereas the CD2071 CD1031 DDC, the CD2071CD103– DDC and the CD207–CD11b– DDC represent quantitatively minor popula-tions (Fig. 1). The remaining CD2071 CD103–DC found in the dermis corre-spond to migratory LCen routeto CLN. Monocytes are rapidly recruited to sites of infections, including the skin, where they convert into ‘‘inflammatory’’ DC (inf-DC) [11, 12]. Inf-DC appear not only to produce high levels of micro-bicidal compounds but also to perform functions distinct from those carried out by the DC present under
non-inflamma-tory conditions. In the absence of inflam-mation, tissues such as the gut and the skin are believed to ‘‘condition’’ DC in a way that prevents DC from inducing Th1 responses [13]. By differentiating from monocytes in an extemporaneous manner, inf-DC might escape such conditioning and thus be the only DC capable of activating effector T cells at the site of infection and, following migration to LN, be the DC capable of polarizing naı¨ve CD41T cells toward a Th1 fate.
Tolerogenic function of steady-state skin DC subsets
Peripheral presentation of self-determi-nants by mig-DC in the absence of inflammation does not prime naı¨ve T cells but rather results in abortive T-cell responses [14]. Consistent with a role in the maintenance of tolerance to skin-derived self-proteins, each of the five identified skin DC subsets migrate to CLN in the absence of inflammation [10, 15]. In steady-state CLN, skin-derived DC express levels of MHC class II (MHCII) molecules and of costimula-tory molecules (CD86 and CD40) that are as high as those found on skin-derived DC that reach CLN under inflammation [4, 16]. Although the expression of peptide–MHC complexes at high levels is consistent with a tolerance-inducing function, the presence of high levels of CD40 and CD86 is paradoxical, given that it has been generally associated with immuno-genic rather than toleroimmuno-genic DC. Sporri
and Reis e Sousa [17] helped to resolve this paradox by demonstrating that indirect activation of DC through inflam-matory signals delivered in ‘‘trans’’ by neighboring cells leads to upregulation of MHCII and costimulatory molecules; however, in contrast to DC stimulated in ‘‘cis’’viaTLR, trans-activated DC lack the ability to produce IL-12 and thus are unable to drive differentiation of CD41T cells into effector cells. Therefore, a ‘‘mature’’ DC phenotype, as defined by high expression of MHCII and costimu-latory molecules, does not necessarily constitute a state of functional maturity, as defined by the ability to induce effector T cells [18, 19]. The sterile triggers that result in the migration of and the upregulation of MHCII and
costimulatory molecules by LC and DDC under steady-state conditions remain, however, to be determined.
CD2071
CD1031
DDC cross-present epidermal self-proteins
A transgenic mouse known as K5.mOVA has been used to determine the relative ability of the various skin DC subsets to cross-present a self-protein expressed in keratinocytes [20]. In K5.mOVA mice, a membrane form of OVA is expressed by skin keratinocytes and in the outer root sheath of hair follicles. Two recent studies based on the K5.mOVA model showed that CD2071CD1031 DDC were the only skin-derived DC able to
cross-present OVA in bothin vitro and in vivo settings [10, 21]. Using mice deficient in LC, it was further shown that CD2071CD1031 DDC cross-present antigen independently of LC [10], which leads to the question of how CD2071CD1031DDC acquire OVA from keratinocytes. CD2071 DDC are often found adjacent to hair follicles [6, 8]. Such an anatomical localization might permit a preferential access to OVA and account in part for the fact that CD2071CD1031DDC constitute the dominant skin mig-DC subset capable of cross-presenting antigen expressed by keratinocytes. The data assigning a preponderant cross-presenting role to CD2071CD1031 DDC [10, 21] remain, however, to be reconciled with earlier
LC migLC DDC CD207 CD103 DDC CD207 CD11b RALDH SKIN Inf-DC Skin-derived migratory DC Lymphoid-tissue resident DC
CUTANEOUS LYMPH NODE CD8α+ CD11b-/low CD11chigh CD207 +/-CD11b+ CD11chigh CD207 -pDC migLC migDDC CD207 CD103 migDDC CD207 CD11b RALDH mig-Inf-DC Inf-DC Cross-presentation of self-proteins expressed
in the skin and of viral antigens to CD8 T cells. Presentation of viral antigens to CD4 T cells.
Induction of contact hypersensitivity.
Presentation of viral antigens to CD4 Tcells. Induction of contact hypersensitivity. RALDH cells trigger induced Treg.
Production of microbicidal compounds (TNF, reactive oxygen
and nitrogen intermediates).
Presentation of pathogen-derived antigens to T cells. Presentation of viral antigens to
CD4 T cells. Induction of contact
hypersensitivity.
Figure 1.Phenotype and function of mouse skin DC subsets. Based on the expression of CD207, CD11b and of CD103, five distinct DC subsets have been identified in mouse steady-state dermis. Due to the fact that these subsets are less well defined and less extensively studied than the other subsets, the CD2071CD103–and CD207–CD11b–DDC have not been represented. CLN contain a migratory counterpart of each of the DC subsets
identified in the skin. Upon skin inflammation, monocytes are rapidly recruited and convert into inf-DC. The functional specialization existing among skin DC subsets is specified in the boxes. All skin DC subsets are capable of inducing delayed type hypersensitivity reactions provided that they have been exposed to the inducing agent [1, 5, 56]. In addition, CLN contain LT-DC that correspond to the CD8a1
, the CD11b1
and the pDC subsets.
results showing that LC are also capable of cross-presenting keratinocyte-expressed antigens [20, 22, 23].
Cross-presentation is also involved in CD81 T-cell responses against viru-ses, the tropism of which is limited to tissue parenchyma. Using HSV-1, Bedouiet al.[21] showed that all skin DC subset can present viral antigens on MHCII molecules. Despite the fact that all skin DC had access to viral antigens, only the CD1031 DDC cross-presented viral antigens efficiently. The disparate cross-presenting ability of CD1031 and CD103–DDC is thus reminiscent of the difference in cross-presenting ability that exists between the CD8a1 and CD8a LT-DC subsets. Therefore, despite the growing number of DC subsets identified in CLN, the CD8a1 LT-DC and the CD2071CD1031 DDC appear to be the only ones dedicated to cross-presentation (Fig. 1).
Role of skin DC in the induction of Foxp31
Treg
The CD1031DC of the lamina propria of the small intestine express retinaldehyde dehydrogenases (RALDH) and produce retinoic acid (RA). Upon migration to mesenteric LN, CD1031 DC confer gut-seeking properties upon antigen-respon-sive T cellsviaproduction of RA [24, 25]. Importantly, RA production by gut-asso-ciated DC is also involved in the genera-tion of induced Foxp31 Treg (iTreg) [13, 26]. Although ‘‘naturally occurring’’ Foxp31 Treg develop in the thymus, iTreg develop de novo in secondary lymphoid organs from conventional naı¨ve CD41 T cells. Conversion from naı¨ve CD41T cells to iTreg can be triggered by DC and requires sub-mitogenic dose of antigen, low costimulation, high levels of TGF-b and is greatly enhanced by the presence of RA. RA production by lamina propria-associated DC has been proposed to maintain the balance between effector and Treg in the gastrointestinal tract and to constitute a major mechanism under-lying oral tolerance [13, 26].
Considering that RALDH expression is the only rate-limiting factor for RA production, Guilliams et al.[27] used a flow cytometry-based assay to measure
RALDH activity at the single-cell level and comprehensively analyzed RA-producing mouse DC populations. RA-producing DC were readily found in the skin and in the lungs, as well as the draining LN of these organs. RA-producing skin-derived DC were capable of triggering the generation of iTreg, which demonstrates that RA-producing tolerogenic DC is not restricted to the intestinal tract. Unexpectedly, the production of RA by skin DC was restricted to the CD207–CD11b1CD103– DDC subset, which suggests that CD103 expression does not constitute a ‘‘univer-sal’’ marker for RA-producing mouse DC. Given that the skin is continuously exposed to antigens, iTreg induced by skin DC might contribute to dampen rampant immune responses to non-self antigens. Therefore, as illustrated for iTreg induction and cross-presentation, distinct functions are performed by different DDC.
Toward a unifying classification of DC subsets across tissues and species
Analysis of the parenchyma of non-lymphoid mouse tissues (intestine, lung, aorta, cardiac valves and liver) has also led to the identification of several distinct DC subsets. Regardless of their anatomical location, some of those DC subsets appear highly related and can be grouped into a handful of major subsets on the basis of their function and of the transcription factors that dictate their development [28, 29]. In thisViewpoint, we propose a unifying classification of DC subsets that not only straddles their primary tissues of resi-dence but also extends across several species.
As shown in Fig. 2, five major DC subsets can be identified in mice and humans: (i) LC, (ii) CD11b1 DC-like cells, (iii) CD8a1 DC-like cells, (iv) plasmacytoid DC (pDC) and (v) monocyte-derived inf-DC [28, 29]. Human and mouse LC are generally considered as equivalent cell types and can be characterized as CD2071 CD11b1cells in both species. Although freshly isolated human LC appear to induce CD81T-cell responses [30], the
function of mouse LC remains to be elucidated [31].
Mouse and human LT-DC comprise three subsets [28, 29, 32] and compar-ison of their respective gene expression programs supports their functional equivalence across the human and mouse species [31, 33]. Based on the transcriptomic [33], functional [30, 34] and developmental [35] studies, mouse CD11b1LT-DC, mouse CD207–CD11b1 mig-DC, human BDCA1(CD1c)1 LT-DC and human CD207–CD141mig-DC can be regrouped as CD11b1 DC-like cells. Those cells have a CADM1–CLEC9A– SIRPa1CD11chigh phenotype and appear dedicated to innate responses against extracellular parasites and to the induction of CD41 T cell and humoral immunity.
Human BDCA31 LT-DC share a distinct gene signature with mouse CD8a1 LT-DC [31, 33]. Both subsets selectively express the membrane markers CADM1 [36], CLEC9A [37–39] and XCR1 [33, 40, 41] but are negative for SIRPa. Interestingly, XCL1, the chemokine ligand for XCR1 is selectively expressed by both activated NK and CD81 T cells [42] and Xcl1 mRNA is stored in central memory CD81 T lymphocytes [41]. Mice deficient for the XCL1-XCR1 chemotactic pathway develop significantly lower CD81 T-cell responses to vaccination with a model antigen [40] or early after infection with Listeria monocytogenes [41]. Hence, the specific expression of XCR1 on mouse CD8a1 LT-DC and human BDCA31 DC likely contributes to their high ability for CD81 T-cell activation [40, 41]. Both human BDCA31 LT-DC and mouse CD8a1 LT-DC express high levels of TLR3 and contain low to undetectable levels of the cytosolic RNA or DNA sensors RIG-I, MDA5 and DAI under steady-state conditions, [43, 44]. In contrast, human BDCA11 and mouse CD11b1 LT-DC express higher levels of PRR involved in bacteria or fungi recog-nition such as TLR1, TLR6, and specific members of the lectin and Nod-like receptor families [43, 45]. Mouse CD103 1
mig-DC share a number of character-istics with CD8a1 LT-DC, including a dependence on Batf3 [46, 47], IRF8 and ID2 [48] for their development. The
DC SUBSETS ORGAN
SPECIES
CD11b -like DC CD8α-like DC pDC inf-DC LC A RY RGANS HUMAN Classical phenotypic definition BDCA1 CD11c ? BDCA2 CD11c -BDCA3 CD11c SECOND A LY MPHOID O L Y M PHOID P ARENC H Y M A CD207 CD14 Classical phenotypic definition CD207 CD14 BDCA1 CD11c ? ? BDCA2 CD11c -CD207 CD14 CD1a BDCA3 CD11c ? NON L TISSUE P CD207 CD14 MOUSE D ARY O RGANS CD207 CD11b CD11c Ly6C MAC3 CD11b CD11c SiglecH CD11c CD207 CD8αand/or CD103 CD11b CD11c Classical phenotypic definition SECON D LY MPHOID O Y MPHOI D A RENC HYMA CD207 CD103 CD11b CD207 CD11b CD11c Ly6C MAC3 CD11b CD11c SiglecH CD11c CD207 CD103 CD11b CD11c NON L Y TISSUE P A Classical phenotypic definition CD207 CD103 CD11b
HUMAN & MOUSE
CADM1 CLEC9A SIRPα CD11c RIG-I/MDA5/DAI NOD/NALP ? CD4 T cell activation, humoral immunity, Awaiting human inf-DC identification TLR4/8 , NOD/NALP ? Innate defenses against infections, TNF & ROI/NOI None? TLR7/9 Innate defenses against viruses, IFN-α/β CADM1 CLEC9A SIRPαCD11c TLR3 ? Cross-presentation, CD8 T cell activation, Proposed unified phenotypic definition Typical PRR Proposed functional specialization CD207 CD11b ? ? response to extracellular parasites IL-12p70
Figure 2.A unifying model of human and mouse DC subsets. Human and mouse DC subsets can be organized into five broad subsets irrespective of their primary location in secondary lymphoid organs or in the parenchyma of non-lymphoid organs. These five subsets correspond to: (i) LC (green), (ii) CD11b1DC-like cells (blue), (iii) CD8
a1DC-like cells (violet), (iv) pDC (brown) and (v) monocyte-derived inf-DC (orange). The phenotype
used to identify those subsets is specified for each condition. A general nomenclature is suggested for each DC subset (lower row, shaded colors), irrespective of their tissue and species of origin. This nomenclature is based on the unified phenotypic definition, characteristic PRR and functional specialization. ROI, radical oxygen intermediates; NOI, nitric oxygen intermediates.
ontogeny of human BDCA31 LT-DC is likely driven by the same pathways as those used by CD8a1 LT-DC, since BDCA31 LT-DC express high levels of Batf3, IRF8 and ID2 mRNA as compared with BDCA11LT-DC [31]. Mouse CD8a1 LT-DC and CD1031 mig-DC are specia-lized in CD81 T-cell activation in parti-cular through cross-presentation [10, 21] and recent reports show that human BDCA31LT-DC are also capable of cross-presentation [41, 49]. Therefore, there exists a common set of properties char-acterizing CD8a1 DC-like cells across tissues and mammalian species, includ-ing a high capacity for cross-presentation and possibly a CADM11CLEC9A1 SIRPa–CD11chighphenotype.
Human and mouse pDC share a number of common features, including a large specific gene expression program [33], a strict dependency for their differ-entiation on the transcription factors Spi-B [50] and E2-2 [51, 52] and a func-tional specialization in innate antiviral defense through high-level production of IFN-a/b in response to TLR7 or TLR9 triggering [53]. Strikingly, apart from their plasmacytoid morphology, it has not been possible to define yet a core pheno-type for mouse and human pDC.
Based on striking similarities in their ontogeny and gene expression programs, the mouse inf-DC observed in vivo are equivalents to the mouse and human DC generated in vitro from monocytic precursors under GM-CSF instruction [33, 54]. Mouse [55] and human inf-DC likely share a critical role during infec-tions through high production of TNF and of reactive oxygen or nitrogen inter-mediates in response to the triggering of TLR4, TLR8 or NOD/NALP family members; however, a unified phenotypic definition of inf-DC is still awaiting their formal identificationin vivoin humans.
Concluding remarks
A number of issues remain to be addressed to fully validate our tentative classification of DC subsets across tissues and mammalian species. They include
(i) a side-by-side comparison of the phenotypes, gene expression programs and proteomes [44, 45]
of mouse CD8a1 LT-DC and CD1031mig-DC,
(ii) a comparative analysis of the functions of human BDCA11 and BDCA31LT-DC and the analysis of the role played by the BATF3, IRF8 and ID2 transcription factors and the FLT3L and M-CSF growth factors during their development, (iii) the investigation of the anatomical
location of human BDCA31DC-like cells in the parenchyma of non-lymphoid tissues and
(iv) the formal identification of human inf-DC in vivo and their functional characterization. Interestingly, the preliminary characterization of DC subsets in other mammalian species, such as sheep, yielded results consis-tent with our DC classification inferred from the comparison of mouse and human [41].
The possibility to identify DC subsets with conserved functionality across tissues and mammalian species should help to identify the core biological pathways and gene networks that specify DC function and to manipulate them in a rational manner.
Acknowledgements:The authors thank Lee Leserman for discussion. This work was supported by CNRS, INSERM, INCA (Melan-Imm project), European Communities Framework Program 7 (MASTERSWITCH Integrating Project HEALTH-F2-2008-223404), ARC (M. D.) and ANR (PhyloGen-DC project, I. S.-C. and M. D.), and by fellowships from ARC (M. G.), European Communities Marie Curie Program (M. G.) and Ministe`re de la Recherche (S. T.).
Conflict of interest:The authors declare no financial or commercial conflict of interest.
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Correspondence: Prof. Bernard Malissen, Centre d’Immunologie de Marseille-Luminy, Campus de Luminy, Case 906, 13288 Marseille, Cedex 09, France
Fax:133-4-91-26-94-30
e-mail: [email protected] Additional correspondence: Dr. Marc Dalod, Centre d’Immunologie de Marseille-Luminy, Campus de Luminy, Case 906, 13288
Marseille, Cedex 09, France. e-mail: [email protected] Received:15/3/2010 Revised:27/4/2010 Accepted:17/5/2010
Key words:DC Human Mouse Skin Subsets
Abbreviations: CLN: LN that drain cutaneous territories DDC: dermal DC inf-DC: inflammatory DC iTreg: induced Foxp31 Treg LC: Langerhans cells LT-DC: lymphoid tissue-resident DC MHCII: MHC class IImig-DC: migratory DCpDC: plasmacytoid DC RA: retinoic acid RALDH: retinaldehyde dehydrogenases See accompanying article:
http://dx.doi.org/10.1002/eji.201040602
Accumulation of plasmacytoid DC: Roles in disease pathogenesis and
targets for immunotherapy
Melissa Swiecki and Marco Colonna
Department of Pathology and Immunology, Washington University School of Medicine,
St. Louis, MO, USA DOI 10.1002/eji.201040602
Plasmacytoid DC (pDC) secrete type I IFN in response to viruses and RNA/ DNA/immunocomplexes. Type I IFN confer resistance to viral infections and promote innate and adaptive immune responses. pDC also produce cytokines and chemokines that influ-ence recruitment and function of T cells and differentiation of B cells. Thus, pDC have been implicated both in protective immune responses and in induction of tolerance. In this
Viewpoint, we discuss how the
recruitment and accumulation of pDC may impact pathogenesis of several diseases and how pDC can be targe-ted for therapeutic interventions.
pDC are type I IFN-producing cells Plasmacytoid DC (pDC) are bone marrow-derived leukocytes that secrete type I IFN (IFN-I) [1, 2]. pDC detect RNA and DNA from viruses and RNA/DNA/
immunocomplexes through two endoso-mal sensors, TLR7 and TLR9, respec-tively, both of which induce secretion of IFN-I through the MyD88-IRF7 signaling pathway [3–5]. pDC were first identified in humans as CD41, CD681and IL-3R1 (CD123) plasma cell-like cells [6]. Initi-ally, it was unclear what functions these cells perform in vivo; however, pDC’s prominent endoplasmic reticulum suggested a role in cytokine secretion. Later, it was demonstrated that this unique subset could differentiate into antigen-presenting cells [7, 8] and specialize in the secretion of IFN-I, thus corresponding to the human natural IFN-producing cells [9, 10]. In 2001, cells that resembled human pDC were finally identified in the mouse [11]. pDC accumulation during infection and disease
pDC originate in the bone marrow from common lymphoid/myeloid progenitors
and are dependent on Flt3L, STAT3 and the transcription factor E2-2 for develop-ment [12]. pDC, similar to committed precursors of classical DC, enter lymphoid organs directly from the blood through the high endothelial venules [13–15]. Under homeostatic conditions, pDC also inhabit mucosal tissues and organs, albeit at low numbers. pDC accumulation in lymphoid tissues, mucosa and organs occurs during several human pathologies, particularly in LN of patients affected by sarcoidosis, Mycobacterium tuberculosisinfection [16], Kikuchi’s disease [17], and in the skin of patients affected by psoriasis [18, 19], systemic lupus erythematosus (SLE) [20] and lichen planus [21, 22]. pDC accumu-lation has also been observed in brain lesions of patients with multiple sclerosis [23], in the salivary glands of patients with Sjogren’s syndrome [24] and the synovia or inflamed muscle tissue/skin of people afflicted with rheumatoid arthritis [25, 26] or dermatomyositis [27, 28], respectively. pDC are over-represented in the blood of