DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling
26 Sep 2011-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 208, Iss: 10, pp 2141-2153
TL;DR: Dermal DC mobilization requires docking to CCL21 on lymphatic endothelium to enable lymphatic DC mobilization to occur on the outside of the Tournaisian barrier.
Abstract: Dendritic cells (DCs) must travel through lymphatics to carry skin antigens into lymph nodes. The processes controlling their mobilization and migration have not been completely delineated. We studied how DCs in live mice respond to skin inflammation, transmigrate through lymphatic endothelium, and propagate in initial lymphatics. At steady state, dermal DCs remain sessile along blood vessels. Inflammation mobilizes them, accelerating their interstitial motility 2.5-fold. CCR7-deficient BMDCs crawl as fast as wild-type DCs but less persistently. We observed discrete depositions of CCL21 complexed with collagen-IV on the basement membrane of initial lymphatics. Activated DCs move directionally toward lymphatics, contact CCL21 puncta, and migrate through portals into the lumen. CCR7-deficient DCs arrive at lymphatics through random migration but fail to dock and transmigrate. Once inside vessels, wild-type DCs use lamellipodia to crawl along lymphatic endothelium and, sensing lymph flow, proceed downstream. DCs start drifting freely only in collecting lymphatics. These results demonstrate in vivo that the CCL21–CCR7 axis plays a dual role in DC mobilization: promoting both chemotaxis and arrest of DCs on lymphatic endothelium. Intralymphatic crawling, in which DCs combine active adhesion-based migration and directional cues from lymph flow, represents a new step in DC mobilization which may be amenable to regulation.
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TL;DR: This review focuses on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
Abstract: Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein–coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
1,475 citations
Cites background from "DC mobilization from the skin requi..."
...CCR7-mediated signals increase the mobility and directional migration of mature DCs toward the lymphatic endothelium (121)....
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...Once in the lumen, they crawl along following the direction of lymphatic flow until they reach the collecting lymphatics, at which point they freely flow with the lymph to the draining LN (121)....
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TL;DR: This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.
Abstract: Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.
795 citations
TL;DR: The emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function is discussed, as well as the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence.
Abstract: Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.
743 citations
TL;DR: Recent progress in the understanding of cDC subset ontogeny and transcription factor dependencies are reviewed, as well as emerging functional specializations within the cDC compartment in lymphoid and nonlymphoid tissues are discussed.
650 citations
Cites background from "DC mobilization from the skin requi..."
...Immobilized CCL21 on, or stored in, lymphatic endothelium plays a critical role in facilitating chemotaxis and arrest of migrating tissue DCs to enter the afferent lymphatics (Tal et al., 2011)....
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TL;DR: Recent advances in understanding of how Rho GTPases contribute to different types of migration are reviewed, comparing lamellipodium-driven versus bleb-driven migration modes and how cells migrate across the endothelium is described.
619 citations
Cites background from "DC mobilization from the skin requi..."
...For example, dendritic cells use lamellipodia to crawl along lymphatic endothelial vessels towards lymph nodes following activation in the tissues [12], and cells at the front of collectively migrating Drosophila border cells extend long Rac-driven lamellipodia [13]....
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References
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TL;DR: Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis and the realization that these cells are a powerful tool for manipulating the immune system is realized.
Abstract: B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.
14,532 citations
"DC mobilization from the skin requi..." refers background in this paper
...As corroborated in knockout mice, without engagement of CCR7 DCs do not enter lymphatics and do not appear in LNs several hours later (Förster et al., 1999; Martín-Fontecha et al., 2003; Ohl et al., 2004)....
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...They are the first cells to appear in draining LNs carrying antigen from the skin (Kamath et al., 2002; Itano et al., 2003; Kissenpfennig et al., 2005), were found to be more motile than LCs in situ (Lindquist et al., 2004; Kissenpfennig et al., 2005; Ng et al., 2008), and proved superior in priming certain immune responses (Helft et al., 2010)....
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...Imaging this area has the the LNs en masse....
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...Based on work in mice deficient in these chemokines, CCL21 seems more important than CCL19 to mobilize skin DCs to LNs (Randolph et al., 2005; Britschgi et al., 2010)....
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...Although the migration of skin DCs to LNs is critical for most vaccination procedures (Romani et al., 2010), the sequence of events regulating their mobilization has not been delineated fully....
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TL;DR: This Review focuses on new aspects of one of the central paradigms of inflammation and immunity — the leukocyte adhesion cascade.
Abstract: To get to the site of inflammation, leukocytes must first adhere to and traverse the blood-vessel wall, events that occur in a cascade-like manner. But what are the exact steps in this cascade and what molecules are involved?
3,917 citations
"DC mobilization from the skin requi..." refers background in this paper
...Notably, within inflamed venules, which, like initial lymphatics, are narrow and slow flowing, leukocytes use an elaborate array of chemokines and adhesion molecules to interact with the endothelium, crawl, and extravasate (Ley et al., 2007)....
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TL;DR: The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II- negative precursors in marrow, and this feature should prove useful for future molecular and clinical studies of this otherwise trace cell type.
Abstract: Antigen-presenting, major histocompatibility complex (MHC) class II-rich dendritic cells are known to arise from bone marrow. However, marrow lacks mature dendritic cells, and substantial numbers of proliferating less-mature cells have yet to be identified. The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II-negative precursors in marrow. A key step is to remove the majority of nonadherent, newly formed granulocytes by gentle washes during the first 2-4 d of culture. This leaves behind proliferating clusters that are loosely attached to a more firmly adherent "stroma." At days 4-6 the clusters can be dislodged, isolated by 1-g sedimentation, and upon reculture, large numbers of dendritic cells are released. The latter are readily identified on the basis of their distinct cell shape, ultrastructure, and repertoire of antigens, as detected with a panel of monoclonal antibodies. The dendritic cells express high levels of MHC class II products and act as powerful accessory cells for initiating the mixed leukocyte reaction. Neither the clusters nor mature dendritic cells are generated if macrophage colony-stimulating factor rather than granulocyte/macrophage colony-stimulating factor (GM-CSF) is applied. Therefore, GM-CSF generates all three lineages of myeloid cells (granulocytes, macrophages, and dendritic cells). Since > 5 x 10(6) dendritic cells develop in 1 wk from precursors within the large hind limb bones of a single animal, marrow progenitors can act as a major source of dendritic cells. This feature should prove useful for future molecular and clinical studies of this otherwise trace cell type.
3,852 citations
"DC mobilization from the skin requi..." refers methods in this paper
...In brief, 4 × 106 cells were cultivated for 13 d in RPMI, supplemented with 10% GM-CSF–conditioned GM-B16 supernatant, which is equivalent to 200 U/ml recombinant mouse GM-CSF (Inaba et al., 1992)....
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TL;DR: This method allows by simple means the generation of high numbers of murine DC with very low B cell or granulocyte contaminations, which will be valuable to study DC biology notably at the molecular level.
2,935 citations
TL;DR: In this paper, the chemokine receptor CCR7 was identified as an important organizer of the primary immune response in mice, and severely delayed kinetics regarding the antibody response and lack contact sensitivity and delayed type hypersensitivity reactions.
2,388 citations