Migratory dendritic cells acquire and present lymphatic endothelial cell-archived antigens during lymph node contraction (original) (raw)
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Vaccinia Virus Infection Inhibits Skin Dendritic Cell Migration to Draining Lymph Node
Despite the success of Vaccinia virus (VACV) against smallpox there remains a paucity of information on Dendritic cell (DC) responses to the virus, especially on the traffic of DCs and VACV to draining LN (dLN). Herein we studied skin DC migration in response to VACV and compared it to the tuberculosis vaccine Mycobacterium bovis Bacille Calmette-Guérin (BCG), another live-attenuated vaccine administered via the skin. In stark contrast to BCG, skin DCs did not relocate to dLN in response to VACV. This happened in spite of virus-induced accumulation of several other innate-immune cell populations in the dLN. UV inactivation of VACV or use of the Modified Vaccinia virus Ankara (MVA) strain promoted DC movement to dLN, indicating that the virus actively interferes with skin DC migration. This active immune suppression by VACV was potent enough to ablate the mobilization of skin DCs in response to BCG, and to reduce the transport of BCG to dLN. Expression of inflammatory mediators assoc...
Journal of Experimental Medicine, 2003
Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7−/− DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation. We also report that DC migration could be increased up to 10-fold by preinjection of inflammatory cytokines that increased the expression of the CCR7 ligand CCL21 in lymphatic endothelial cells. The magnitude and quality of CD4+ T cell response was proportional to the number of antigen-carrying DCs that reached the lymph node and could be boosted up to 40-fold by preinjection of tumor n...
Vaccinia Virus Infection Inhibits Skin Dendritic Cell Migration to the Draining Lymph Node
The Journal of Immunology Author Choice, 2021
Key Points Replication-competent VACV inhibits skin DC migration to draining lymph node. The VACV-suppressive effect is a general phenomenon of VACV infection in the skin. VACV can access the lymph node in the absence of DC transport and prime CD4+ T cells. Visual Abstract There is a paucity of information on dendritic cell (DC) responses to vaccinia virus (VACV), including the traffic of DCs to the draining lymph node (dLN). In this study, using a mouse model of infection, we studied skin DC migration in response to VACV and compared it with the tuberculosis vaccine Mycobacterium bovis bacille Calmette–Guérin (BCG), another live attenuated vaccine administered via the skin. In stark contrast to BCG, skin DCs did not relocate to the dLN in response to VACV. Infection with UV-inactivated VACV or modified VACV Ankara promoted DC movement to the dLN, indicating that interference with skin DC migration requires replication-competent VACV. This suppressive effect of VACV was capable of m...
Immunity, 2006
Skin dendritic cells (DCs) are thought to act as key initiators of local T cell immunity. Here we show that after skin infection with herpes simplex virus (HSV), cytotoxic T lymphocyte (CTL) activation required MHC class I-restricted presentation by nonmigratory CD8 + DCs rather than skin-derived DCs. Despite a lack of direct presentation by migratory DCs, blocking their egress from infected skin substantially inhibited class I-restricted presentation and HSV-specific CTL responses. These results support the argument for initial transport of antigen by migrating DCs, followed by its transfer to the lymphoid-resident DCs for presentation and CTL priming. Given that relatively robust CTL responses were seen with small numbers of skinemigrant DCs, we propose that this inter-DC antigen transfer functions to amplify presentation across a larger network of lymphoid-resident DCs for efficient T cell activation.
Journal of Experimental Medicine, 2000
Antigen transport from the airway mucosa to the thoracic lymph nodes (TLNs) was studied in vivo by intratracheal instillation of fluorescein isothiocyanate (FITC)-conjugated macromolecules. After instillation, FITC ϩ cells with stellate morphology were found deep in the TLN T cell area. Using flow cytometry, an FITC signal was exclusively detected in CD11c med-hi /major histocompatibility complex class II (MHCII) hi cells, representing migratory airway-derived lymph node dendritic cells (AW-LNDCs). No FITC signal accumulated in lymphocytes and in a CD11c hi MHCII med DC group containing a CD8 ␣ hi subset (non-airway-derived [NAW]-LNDCs). Sorted AW-LNDCs showed long MHCII bright cytoplasmic processes and intracytoplasmatic FITC ϩ granules. The fraction of FITC ϩ AW-LNDCs peaked after 24 h and had reached baseline by day 7. AW-LNDCs were depleted by 7 d of ganciclovir treatment in thymidine kinase transgenic mice, resulting in a strong reduction of FITC-macromolecule transport into the TLNs. Compared with intrapulmonary DCs, AW-LNDCs had a mature phenotype and upregulated levels of MHCII, B7-2, CD40, and intracellular adhesion molecule (ICAM)-1. In addition, sorted AW-LNDCs from FITC-ovalbumin (OVA)-instilled animals strongly presented OVA to OVA-TCR transgenic T cells. These results validate the unique sentinel role of airway DCs, picking up antigen in the airways and delivering it in an immunogenic form to the T cells in the TLNs.
Activation of bone marrow–resident memory T cells by circulating, antigen-bearing dendritic cells
Nature Immunology, 2005
Dendritic cells (DC) carry antigen from peripheral tissues via lymphatics to lymph nodes (LN). We report that differentiated DC can also travel from the periphery into the blood. Circulating DC migrated to the spleen, liver and lung, but not LN. They also homed to the bone marrow (BM) where they were better retained than in most other tissues. DC homing to the BM depended on constitutively expressed VCAM-1 and endothelial selectins in BM microvessels. Two-photon intravital microscopy in BM cavities revealed that DC formed stable antigen-dependent contacts with BM-resident central memory T cells. Moreover, using this novel migratory pathway, antigen-pulsed DC could trigger central memory T cell-mediated recall responses in the BM.
F1000 - Post-publication peer review of the biomedical literature, 2005
Dendritic cells (DC) carry antigen from peripheral tissues via lymphatics to lymph nodes (LN). We report that differentiated DC can also travel from the periphery into the blood. Circulating DC migrated to the spleen, liver and lung, but not LN. They also homed to the bone marrow (BM) where they were better retained than in most other tissues. DC homing to the BM depended on constitutively expressed VCAM-1 and endothelial selectins in BM microvessels. Two-photon intravital microscopy in BM cavities revealed that DC formed stable antigen-dependent contacts with BM-resident central memory T cells. Moreover, using this novel migratory pathway, antigen-pulsed DC could trigger central memory T cell-mediated recall responses in the BM. Dendritic cells (DC) are key players in innate and adaptive immune responses 1. The prevalent model of DC migration is an unidirectional pathway whereby precursor DC arise from progenitors in the bone marrow (BM), enter the blood and traffic into secondary lymphoid organs (SLO) and peripheral tissues, such as skin or gut 2 , where they contribute to the frontline of defense against pathogens. When DC encounter inflammatory stimuli, they undergo a switch in chemokine receptor expression enabling their egress into lymphatic vessels and transport to draining lymph nodes (LN) 3. Maturing DC also become fully immuno-stimulatory by up-regulating major histocompatibility complex (MHC) and costimulatory molecules to prime naïve T cells. Normal peripheral blood contains some immature DC, which capture blood-borne bacteria and transport them to the spleen 4. However, whether these DC originate directly in the BM or reenter the blood after migrating within other tissues is unclear. There is ample experimental evidence that draining LN are the terminal targets for most DC that leave peripheral tissues. However, a few observations suggest that tissue-resident DC can somehow return to the blood and carry antigen (Ag) to organs other than LN. For example, DC carry fluorescent beads, dyes or Ag to the spleen after either i.c. injection or instillation into the lung 5-7. However, whether and to what extent blood-borne DC carry Ag to other tissues is unclear. This question has
The Journal of Immunology, 2009
In vivo data suggest that monocytes participate critically in cross-presentation, but other data suggest that lymph node resident dendritic cells (DCs) mainly cross-present. Here, we utilized a three-dimensional model of a blood vessel wall that endogenously supports DC development from human monocytes, and we incorporated dying autologous cells in the subendothelial matrix of the model. Flu-infected dying cells promoted monocytes to become mature DCs and cross-present cell-associated Ags for the activation of CTLs. Similar responses were induced by loading the dying cells with the TLR7/8 ligand ssRNA, whereas dying cells loaded with TLR3 ligand were less efficient. Monocyte-derived DCs that developed in this model cross-presented Ag to T cells efficiently regardless of whether they engulfed detectable amounts of labeled dying cells. Unexpectedly, the monocyte-derived cells that directly engulfed dying cells in vitro were not the major APCs stimulating CD8 ؉ lymphocytes. Instead, bystander DCs acquired more robust capacity to cross-prime through receipt of MHC class I/peptide from the phagocytic, monocyte-derived cells. In mice, lymph node-homing monocyte-derived DCs processed Ags from engulfed cells and then transferred MHC class I/peptide complexes to confer cross-priming capacity to MHC class I-deficient lymph node resident CD8␣ ؉ DCs. Thus, natural or synthetic TLR7/8 agonists contained within dying cells promote the conversion of monocytes to DCs with capacity for cross-presentation and for "cross-dressing" other DCs. These data reveal a way in which migratory monocyte-derived DCs and other DCs, like lymph node resident DCs, both mediate cross-presentation.
Dendritic cells: driving the differentiation programme of T cells in viral infections
Immunology and Cell Biology, 2008
Protective immunity against viral pathogens depends on the generation and maintenance of a small population of memory CD8 + T cells. Successful memory cell generation begins with early interactions between naïve T cell and dendritic cells (DCs) within the inflammatory milieu of the secondary lymphoid tissues. Recent insights into the role of different populations of DCs, and kinetics of antigen presentation, during viral infections have helped to understand how DCs can shape the immune response. Here, we review the recent progress that has been made towards defining how specific DC subsets drive effector CD8 + T-cell expansion and differentiation into memory cells. Further, we endeavour to examine how the molecular signals imparted by DCs coordinate to generate protective CD8 + T-cell immunity.