scholarly journals Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity

2021 ◽  
Vol 118 (3) ◽  
pp. e2021364118
Author(s):  
Hannah L. Miller ◽  
Prabhakar Sairam Andhey ◽  
Melissa K. Swiecki ◽  
Bruce A. Rosa ◽  
Konstantin Zaitsev ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Diphtheria Toxin ◽  
Fluorescein Isothiocyanate ◽  
Skin Inflammation ◽  
Contact Hypersensitivity ◽  
Type I ◽  
Th2 Response ◽  
Draining Lymph Nodes

Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR+ mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+ CD103+ cDC1 and more Th2-priming CD11b+ cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+ cDCs revealed that CD326+ DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+ DCs did not express Tcf4, DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.

scholarly journals Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity

2005 ◽  
Vol 169 (4) ◽  
pp. 569-576 ◽  
Author(s):  
Clare L. Bennett ◽  
Erwin van Rijn ◽  
Steffen Jung ◽  
Kayo Inaba ◽  
Ralph M. Steinman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Steady State ◽  
Diphtheria Toxin ◽  
Langerhans Cells ◽  
Contact Hypersensitivity ◽  
Relative Importance ◽  
Skin Immunity

Langerhans cells (LC) form a unique subset of dendritic cells (DC) in the epidermis but so far their in vivo functions in skin immunity and tolerance could not be determined, in particular in relation to dermal DC (dDC). Here, we exploit a novel diphtheria toxin (DT) receptor (DTR)/DT-based system to achieve inducible ablation of LC without affecting the skin environment. Within 24 h after intra-peritoneal injection of DT into Langerin-DTR mice LC are completely depleted from the epidermis and only begin to return 4 wk later. LC deletion occurs by apoptosis in the absence of inflammation and, in particular, the dDC compartment is not affected. In LC-depleted mice contact hypersensitivity (CHS) responses are significantly decreased, although ear swelling still occurs indicating that dDC can mediate CHS when necessary. Our results establish Langerin-DTR mice as a unique tool to study LC function in the steady state and to explore their relative importance compared with dDC in orchestrating skin immunity and tolerance.

scholarly journals Specific Migratory Dendritic Cells Rapidly Transport Antigen from the Airways to the Thoracic Lymph Nodes

2000 ◽  
Vol 193 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Karim Y. Vermaelen ◽  
Ines Carro-Muino ◽  
Bart N. Lambrecht ◽  
Romain A. Pauwels
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Nodes ◽  
Intratracheal Instillation ◽  
Fluorescein Isothiocyanate ◽  
Airway Mucosa ◽  
Macromolecule Transport ◽  
Intracellular Adhesion Molecule ◽  
Fitc Signal

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+ cells with stellate morphology were found deep in the TLN T cell area. Using flow cytometry, an FITC signal was exclusively detected in CD11cmed-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 CD11chiMHCIImed DC group containing a CD8αhi subset (non–airway-derived [NAW]-LNDCs). Sorted AW-LNDCs showed long MHCIIbright cytoplasmic processes and intracytoplasmatic FITC+ granules. The fraction of FITC+ 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.

Dynamic accumulation of plasmacytoid dendritic cells in lymph nodes is regulated by interferon-β

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2623-2631 ◽  
Author(s):  
Yunfei Gao ◽  
Beata Majchrzak-Kita ◽  
Eleanor N. Fish ◽  
Jennifer L. Gommerman
Keyword(s):  
Dendritic Cells ◽  
Virus Infection ◽  
Lymph Nodes ◽  
Viral Infection ◽  
Ex Vivo ◽  
Plasmacytoid Dendritic Cells ◽  
Lymphoid Organs ◽  
Type I ◽  
Secondary Lymphoid Organs

Abstract Plasmacytoid dendritic cells (pDCs) represent a major cellular component of our front-line defense against viruses because of their capacity to rapidly secrete type I interferon (IFN)–α and -β after infection. Constant immunosurveillance of the host requires that lymphocytes traffic through lymph nodes (LNs) to sample antigen, yet little is known about the dynamics of pDC accumulation within the secondary lymphoid organs. Here we show that pDCs readily accumulate within the secondary lymphoid organs of mice after virus infection. Interestingly, retention of pDC within LNs is enhanced in the presence of the sphingoshine-1-phosphate receptor agonist FTY720 in a manner similar to that observed for B and T lymphocytes. Ex vivo comparison of mouse pDCs with lymphocytes revealed that pDCs express sphingoshine-1-phosphate 4 and also constitutively express CD69, which is further up-regulated upon virus infection. In IFN-β−/− mice, accumulation of pDC and lymphocytes within LNs is reduced both during viral infection and under steady state conditions, and these defects can be reversed by adding recombinant IFN-β in vivo. These data suggest that pDC and lymphocytes use similar mechanisms for retention within LNs and that these processes are influenced by IFN-β even in the absence of viral infection.

Disrupted homeostasis of Langerhans cells and interdigitating dendritic cells in monkeys with AIDS

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2859-2868 ◽  
Author(s):  
Michael I. Zimmer ◽  
Adriana T. Larregina ◽  
Cielo M. Castillo ◽  
Saverio Capuano ◽  
Louis D. Falo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Langerhans Cells ◽  
Receptor Expression ◽  
Peripheral Tissues ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Draining Lymph Nodes

Abstract Langerhans cells (LCs) are immature dendritic cells (DCs) that capture antigen in peripheral tissues and migrate to draining lymph nodes, where they reside in the paracortex as interdigitating dendritic cells (IDCs). We studied the effects of simian immunodeficiency virus (SIV) on LCs and IDCs during different stages of infection in monkeys. LCs isolated from monkeys with acute SIV infection or acquired immunodeficiency syndrome (AIDS) underwent normal maturation in vitro, including a switch in chemokine receptor expression from CCR5 to CXCR4 and CCR7. LCs migrated normally from skin in response to contact sensitization in monkeys with acute SIV infection. In contrast, LC migration from skin was markedly impaired during AIDS, associated with a reduction in antigen-bearing DCs in draining lymph nodes. Lymph node IDCs were increased in proportion during acute SIV infection and had an activated phenotype, whereas during AIDS IDCs had significantly lower expression of CD40 and the activation marker CD83. IDCs from monkeys with AIDS were refractory to stimulation with CD40L, demonstrating a functional consequence of decreased CD40 expression. SIV-infected DCs were not identified in lymph nodes or skin of monkeys with AIDS, suggesting an indirect effect of infection on DC populations in vivo. These data indicate that DCs are mobilized to lymph nodes during acute SIV infection, but that during AIDS this process is suppressed, with LC migration and IDC activation being impaired. We conclude that disruption of DC homeostasis may play a role in immunopathology induced by human immunodeficiency virus and suggest that therapeutic strategies targeting DCs may have limited efficacy during AIDS.

scholarly journals Trance, a Tumor Necrosis Factor Family Member, Enhances the Longevity and Adjuvant Properties of Dendritic Cells in Vivo

2000 ◽  
Vol 191 (3) ◽  
pp. 495-502 ◽  
Author(s):  
Régis Josien ◽  
Hong-Li Li ◽  
Elizabeth Ingulli ◽  
Supria Sarma ◽  
Brian R.Wong ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Lymph Nodes ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
T Cell Priming ◽  
Draining Lymph Nodes ◽  
Necrosis Factor

Mature dendritic cells (DCs) are powerful antigen presenting cells that have the unique capacity to migrate to the T cell zone of draining lymph nodes after subcutaneous injection. Here we report that treatment of antigen-pulsed mature DCs with tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a TNF family member, before immunization enhances their adjuvant capacity and elicits improved T cell priming in vivo, such that both primary and memory T cell immune responses are enhanced. By enumerating migratory DCs in the draining lymph nodes and by studying their function in stimulating naive T cells, we show that one of the underlying mechanisms for enhanced T cell responses is an increase in the number of ex vivo antigen-pulsed DCs that are found in the T cell areas of lymph nodes. These results suggest that the longevity and abundance of mature DCs at the site of T cell priming influence the strength of the DC-initiated T cell immunity in situ. Our findings have the potential to improve DC-based immunotherapy; i.e., the active immunization of humans with autologous DCs that have been pulsed with clinically significant antigens ex vivo.

scholarly journals Cd40–Cd40 Ligand Interactions in Vivo Regulate Migration of Antigen-Bearing Dendritic Cells from the Skin to Draining Lymph Nodes

1999 ◽  
Vol 191 (11) ◽  
pp. 2011-2020 ◽  
Author(s):  
Angus M. Moodycliffe ◽  
Vijay Shreedhar ◽  
Stephen E. Ullrich ◽  
Jeffrey Walterscheid ◽  
Corazon Bucana ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Cd40 Ligand ◽  
Vital Role ◽  
Contact Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Tnf Α ◽  
Ligand Interactions ◽  
Draining Lymph Nodes

Whereas CD40–CD40 ligand interactions are important for various dendritic cell (DC) functions in vitro, their in vivo relevance is unknown. We analyzed the DC status of CD40 ligand −/− mice using a contact hypersensitivity (CHS) model system that enables multiple functions of DCs to be assessed in vivo. Immunohistochemistry of skin sections revealed no differences in terms of numbers and morphology of dendritic epidermal Langerhans cells (LCs) in unsensitized CD40 ligand −/− mice as compared with wild-type C57BL/6 mice. However, after contact sensitization of CD40 ligand −/− mice, LCs failed to migrate out of the skin and substantially fewer DCs accumulated in draining lymph nodes (DLNs). Furthermore, very few antigen-bearing DCs could be detected in the paracortical region of lymph nodes draining sensitized skin. This defect in DC migration after hapten sensitization was associated with defective CHS responses and decreased cutaneous tumor necrosis factor (TNF)-α production and was corrected by injecting recombinant TNF-α or an agonistic anti-CD40 monoclonal antibody. Thus, CD40–CD40 ligand interactions in vivo regulate the migration of antigen-bearing DCs from the skin to DLNs via TNF-α production and play a vital role in the initiation of acquired T cell–mediated immunity.

scholarly journals Lymphocytoid Choriomeningitis Virus Activates Plasmacytoid Dendritic Cells and Induces a Cytotoxic T-Cell Response via MyD88

2007 ◽  
Vol 82 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Andreas Jung ◽  
Hiroki Kato ◽  
Yutaro Kumagai ◽  
Himanshu Kumar ◽  
Taro Kawai ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Intracellular Signaling ◽  
Plasmacytoid Dendritic Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Type I ◽  
Ctl Response ◽  
Type I Ifns ◽  
Lcmv Infection

ABSTRACTToll-like receptors (TLRs) and retinoic acid-inducible gene I-like helicases (RLHs) are two major machineries recognizing RNA virus infection of innate immune cells. Intracellular signaling for TLRs and RLHs is mediated by their cytoplasmic adaptors, i.e., MyD88 or TRIF and IPS-1, respectively. In the present study, we investigated the contributions of TLRs and RLHs to the cytotoxic T-lymphocyte (CTL) response by using lymphocytoid choriomeningitis virus (LCMV) as a model virus. The generation of virus-specific cytotoxic T lymphocytes was critically dependent on MyD88 but not on IPS-1. Type I interferons (IFNs) are known to be important for the development of the CTL response to LCMV infection. Serum levels of type I IFNs and proinflammatory cytokines were mainly dependent on the presence of MyD88, although IPS-1−/−mice showed a decrease in IFN-α levels but not in IFN-β and proinflammatory cytokine levels. Analysis ofIfna6+/GFPreporter mice revealed that plasmacytoid dendritic cells (DCs) are the major source of IFN-α in LCMV infection. MyD88−/−mice were highly susceptible to LCMV infection in vivo. These results suggest that recognition of LCMV by plasmacytoid DCs via TLRs is responsible for the production of type I IFNs in vivo. Furthermore, the activation of a MyD88-dependent innate mechanism induces a CTL response, which eventually leads to virus elimination.

scholarly journals In vivo two-photon imaging of T cell motility in joint-draining lymph nodes in a mouse model of rheumatoid arthritis

2012 ◽  
Vol 278 (1-2) ◽  
pp. 158-165 ◽  
Author(s):  
Tamás Kobezda ◽  
Sheida Ghassemi-Nejad ◽  
Tibor T. Glant ◽  
Katalin Mikecz
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Mouse Model ◽  
Lymph Nodes ◽  
Cell Motility ◽  
Two Photon ◽  
Photon Imaging ◽  
Two Photon Imaging ◽  
Draining Lymph Nodes

Morin Promotes the Production of Th2 Cytokine by Modulating Bone Marrow-Derived Dendritic Cells

2006 ◽  
Vol 34 (04) ◽  
pp. 667-684 ◽  
Author(s):  
Chia-Yang Li ◽  
Jau-Ling Suen ◽  
Bor-Luen Chiang ◽  
Pei-Dawn Lee Chao ◽  
Shih-Hua Fang
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Interleukin 12 ◽  
Th2 Response ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Th Differentiation ◽  
Th1 And Th2 Responses

Our previous studies had reported that morin decreased the interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-activated macrophages, suggesting that morin may promote helper T type 2 (Th2) response in vivo. Dendritic cells (DCs) are the most potent antigen presenting cells and known to play a major role in the differentiation of helper T type 1 (Th1) and Th2 responses. This study aimed to reveal whether morin is able to control the Th differentiation through modulating the maturation and functions of DCs. Bone marrow-derived dendritic cells (BM-DCs) were incubated with various concentrations of morin and their characteristics were studied. The results indicated that morin significantly affects the phenotype and cytokine expression of BM-DCs. Morin reduced the production of IL-12 and TNF-α in BM-DCs, in response to LPS stimulation. In addition, the proliferative response of stimulated alloreactive T cells was significantly decreased by morin in BM-DCs. Furthermore, allogeneic T cells secreted higher IL-4 and lower IFN-γ in response to morin in BM-DCs. In conclusion, these results suggested that morin favors Th2 cell differentiation through modulating the maturation and function of BM-DCs.

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