CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues

Abstract

Absent in peripheral tissues during homeostasis, human plasmacytoid dendritic cells (pDCs) are described in inflamed skin or mucosa. Here, we report that, unlike blood pDCs, a subset of tonsil pDCs express functional CCR6 and CCR10, and their respective ligands CCL20 and CCL27are detected in inflamed epithelia contacting blood dendritic cell antigen 2 ؉ pDCs. Moreover, pDCs are recruited to imiquimod-treated skin tumors in WT but not CCR6-deficient mice, and competitive adoptive transfers reveal that CCR6-deficient pDCs are impaired in homing to inflamed skin tumors after intravenous transfer. On IL-3 culture, CCR6 and CCR10 expression is induced on human blood pDCs that become responsive to CCL20 and CCL27/ CCL28, respectively. Interestingly, unlike myeloid DC, blood pDCs initially upregulate CCR7 expression and CCL19 responsiveness on IL-3 ؎ CpG-B and then acquire functional CCR6 and CCR10. Finally, IL-3-differentiated CCR6 ؉ CCR10 ؉ pDCs secrete high levels of IFN-␣ in response to virus. Overall, we propose an unexpected pDCs migratory model that may best apply for mucosal-associated lymphoid tissues. After CCR7-mediated extravasation into lymphoid tissues draining inflamed epithelia, blood pDCs may be instructed to up-regulate CCR6 and/or CCR10 allowing their homing into inflamed epithelia (in mucosae or skin IntroductionPlasmacytoid dendritic cells (pDCs) play an important role in innate antiviral immunity by rapidly secreting abundant type I IFNs after exposure to various RNA or DNA viruses. 1 This unique ability is mediated through their selective expression of TLR7 and TLR9, 2 involved in pathogen sensing. After activation, pDCs differentiate into a distinct type of mature DCs directing T-cell responses with high flexibility. 1 Thus, pDCs play a critical role at the interface between innate and adaptive immunity.pDCs are commonly detected in peripheral blood and lymphoid organs. 1 Unlike myeloid DC (mDCs), they are absent from peripheral epithelial tissues under steady-state conditions, fail to migrate in response to inflammatory chemokines in vitro, and are constitutively recruited from the blood to the lymph nodes through high endothelial venule, a process involving CD62L, CCR7, ChemR23, and CXCR3/4. 3-10 On maturation, both DC subsets up-regulate CCR7 expression and respond to the lymph nodehoming chemokines CCL19 and CCL21, 5,7,8 allowing their recruitment in T-cell areas where they initiate adaptive immune responses. It was recently shown in mice that CCR7 plays an essential role for the homing of pDCs, regardless of their activation status, to lymph node under both steady-state and inflammatory conditions. 10However, pDCs also accumulate in inflamed epithelial tissues during noninfectious and infectious disorders 9,11-18 and participate in inflammatory chronic diseases, such as psoriasis and systemic lupus erythematosus. 14,19,20 Moreover, pDC leukemia/lymphoma is often associated with isolated cutaneous lesions because of skin accumulation of leukemic pDCs. 21 Inducible CXCR3 ligands (CXCL9/10/11...

CCL20/CCR6 Signaling Regulates Bone Mass Accrual in Mice

“…With respect to potential paracrine effects, CCR6 expression has been reported in various immune cells found within the bone environment, and CCL20 has been shown to stimulate chemotaxis in these cells. (5)(6)(7) Our data indicate that osteoblasts are able to recruit both BMM and T cells, at least in part through CCL20/CCR6 signaling. Given the reported ability of BMM and T cells to promote osteoblast differentiation and survival, (26,29,33) diminished recruitment of these immune cells may also contribute to the observed low-bone phenotype.…”

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…In steady state, PDC reside mainly in T cell-rich areas in lymph nodes and secondary lymphoid organs 7 . Localizations of PDC in other lymphoid organs, such as Peyer’s patches of the gut 22 , and tonsils 23 , have been reported. PDC residing in non-lymphoid tissue – such as the airways 24 and the liver 25 – exert a critical role in steady state by regulating mucosal immunity and maintaining tolerance to inhaled or ingested antigens 26 .…”

“…Finally, PDC are also present in the thymus during homeostatic conditions, where they play a role in central tolerance 27– 29 . In contrast, during infections or autoimmune diseases, PDC migrate to inflamed lymph nodes 14 or inflamed epithelia 14, 23, 30 . The microenvironment in which PDC are present may influence oxygen and nutrient availability, which impacts on metabolic pathways (see section 3).…”

Plasmacytoid dendritic cells lead the charge against tumors

“…Imiquimod's dual role: controlling "attraction" and "activation" The pattern of pDC migration reflects a complex interchange between chemokine receptor expression by pDCs and chemokine secretion in lymph nodes and inflamed tissues (14). In blood, pDCs, either constitutively or following activation, express CCR7 and respond to CCL21 in high endothelial venules, allowing them to home to lymph nodes.…”

“…This pattern of pDC migration is consistent with the concept that pDCs become activated in a sequential fashion. Besides CCL2, imiquimod induces the production of the chemokine ligands for CXCR3 (15) and the skin-homing chemokine CCL20 (14). A recent study suggested that upregulation of CCR6 and CCR10 (the receptors for CCL20 and CCL27/28) on pDCs is crucial for imiquimod-dependent pDC migration to the skin (14), although the relevance of CCL20 and whether CCR6-expressing pDCs acquire a killer phenotype was not investigated in the model studied by Drobits et al Tumors including melanomas also produce chemokines that attract pDCs (16), but these may not activate their antitumor potential.…”