Dendritic cell heterogeneity – also a matter of residence
DCs are pivotal decision makers in the balance between tolerance and immunity. Upon activation through pattern recognition receptor (PRR) signaling, they undergo maturation specific transcriptional changes that subsequently allow for the activation of effector cells, including T cells and B cells. DCs comprise a very heterogeneous family; they can generally be divided into conventional DCs (cDC) and plasmacytoid DCs (pDC). cDCs represent the classical DC subset; they are fast in antigen uptake and can efficiently present antigen to naïve T cells. DCs are highly capable to adapt to their microenvironment. In order to sense their surroundings and to react accurately, DCs express a huge variety of different receptors, like PRRs, cytokine receptors, chemokine receptors and NRs. We have shown that pDCs and cDCs from different lymphoid tissues, like spleen, bone marrow (BM), skin draining lymph nodes (SLN) and mesenteric lymph nodes (MLN) express the same repertoire of NRs (chapter 2). Moreover, mRNA levels of the different NRs within one DC subset were quite stable when compared between the organs. Different studies have shown that DCs from distinct tissues display characteristic functional responses towards pathogenic stimuli.1-7 Proietto et al. demonstrated that CD8α+ cDCs, CD8α- cDCs and pDCs from the spleen markedly differed in their production of cytokines/chemokines and in their ability to prime naïve T cells compared to their respective counterparts in the thymus.5 Remarkably, all three subsets from the thymus showed enhanced secretion of CCL-17, CCL-21, CCL-22 and CCL-25. As the individual subsets from both tissues expressed comparable levels of TLRs, it is likely that the difference in functional responses can be allocated to tissue specific microenvironmental factors, like hormones and vitamins. cDCs and pDCs from spleen and thymus are likely to express the same NR repertoire. The distinct composition of a given microenvironment will therefore potentially determine the immune response of the DCs rather than the cells’ receptor expression profile. The concept that the heterogeneity within a given DC subset is a matter of residency is further supported by the distinct functional characteristics of DCs in mucosal organs like the gut and skin.8,9 Vitamin A (VitA) is now well known to be necessary for optimal cDC function in MLNs and in the microenvironment of the gut.10-12 Epithelial cells of the gut
and stromal cells of the local MLNs secrete the VitA metabolite retinoic acid (RA) and thereby imprint the resident CD103+ intestinal DCs with their unique tolerogenic properties.11 A hallmark of this imprinting is the expression of the RA metabolizing enzyme retinal aldehyde dehydrogenase (RALDH).13,14 RA conditioned CD103+ DCs then produce RA themselves, a pivotal factor for the attraction of gut-homing regulatory T cells (Treg).15 The signaling of RA through the retinoid acid receptor (RAR) is therefore pivotal for the homeostasis of the tolerogenic microenvironment in the gut. Similar to the gut, the skin is a part of the first line of defense and also harbors various DCs, including the epidermal Langerhans cells (LC) and dermal DCs (DDC). Sunlight induced vitamin D (VitD) is a key environmental factor in the skin, responsible for the imprinting of skin resident DCs to promote epidermotropism of T cells.16 DCs in the skin express the VitD metabolizing enzymes Cyp27A1 and Cyp27B1 and actively convert VitD precursors to the active ligand calcitriol. The DC secreted calcitriol then binds to the VitD receptor (VDR) in the T cells and induces the expression of skin homing chemokine receptor CCR10, enabling the T cells to migrate towards the keratinocyte excreted CCL27.16
In conclusion, DC heterogeneity is not only a matter of distinct subsets but also of tissue residence. Microenvironmental factors, like hormones and vitamins, play key roles in the orchestration of DC mediated immune responses in tissues like the gut and skin. Moreover, DCs themselves metabolize and secrete hormones and vitamins, i.e. VitA and VitD, to further coordinate T cell responses.
Nuclear receptors in dendritic cell subsets
pDCs comprise a unique DC subset, they are well known for their rapid and vast production of interferon alpha (IFNα). Yet, like cDCs, activated pDCs are efficient in antigen uptake, processing and presentation.17,18 Despite the appreciated effects of NR ligand stimulation on cDCs, very little is known regarding the expression and function of NRs in pDCs. In chapter 2 we compared the NR expression profile of cDCs and pDCs. Our data show that both DC subsets expressed the same NR repertoire, in vitro and ex vivo. The mRNA expression levels of individual receptors, however, differed between cDCs and pDCs, especially upon maturation with toll like receptor (TLR) ligands. These data indicate that NR expression in DCs is regulated in a subset specific manner and that NR ligand stimulation might differentially affect the function of cDCs and pDCs.
The heterogeneous DC family extends beyond cDCs and pDCs. In human blood, cDCs can be further sub-divided into BDCA-1 (CD1c), BDCA-3 and CD16 expressing DCs. These three cDC subsets share the ability to produce IL-12 upon recognition of pathogen associated molecular patterns (PAMP). Yet, they distinctly differ in their expression of PRRs, production of cytokines/chemokines and T cell stimulating capacity.19,20 In the murine system, at least three cDC subsets are distinguished in the spleen: CD8α+/CD4-, CD8α-/CD4+ and double negative CD8α-/CD4- cDCs.21 These three murine cDC subsets each express a characteristic PRR repertoire and show distinct responses towards pathogenic stimuli.22,23 In addition to these migratory DCs, human and murine organs harbor tissue-resident DC subsets, like langerhans cells in the skin or CD103+ cDCs in the gut lamina propria. Little is known regarding the NR expression between the different cDC subsets. Given that murine cDCs (in general) and pDCs express an identical NR repertoire (chapter 2); it is tempting to speculate that the individual cDC subsets share the same NR profile as well. Resting DCs will therefore be shaped by the microenvironment of the tissue in which they reside. The expression dynamics of the NRs, however, are likely to differ between cDC subsets upon maturation, as seen for cDCs and pDCs. Inflammatory conditions induce distinct transcriptional responses in DCs to ensure that the cells can react appropriately and elicit efficient immune responses. We show that cDCs and pDCs regulate NR
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expression levels upon maturation with TLR ligands. Therefore, it would be interesting to compare the NR expression profile of the different cDC subsets in steady state and following PRR stimulation.