Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes

Immunotherapy ◽  
2009 ◽  
Vol 1 (4) ◽  
pp. 539-547
Author(s):  
Nancy I Kerkvliet ◽  
Linda B Steppan ◽  
William Vorachek ◽  
Shannon Oda ◽  
David Farrer ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Aryl Hydrocarbon Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Autoimmune Encephalitis ◽  
Nod Mice ◽  
Aryl Hydrocarbon ◽  
Immune Mediated ◽  
Tcdd Treatment ◽  
Pancreatic Lymph Nodes

The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is a novel inducer of adaptive Tregs. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most potent AHR ligand, induces adaptive CD4+CD25+ Tregs during an acute graft-versus-host (GvH) response and prevents the generation of allospecific cytotoxic T lymphocytes. TCDD also suppresses the induction of experimental autoimmune encephalitis in association with an expanded population of Foxp3+ Tregs. In this study, we show that chronic treatment of NOD mice with TCDD potently suppresses the development of autoimmune Type 1 diabetes in parallel with greatly reduced pancreatic islet insulitis and an expanded population of CD4+CD25+Foxp3+ cells in the pancreatic lymph nodes. When treatment with TCDD was terminated after 15 weeks (23 weeks of age), mice developed diabetes over the next 8 weeks in association with lower numbers of Tregs and decreased activation of AHR. Analysis of the expression levels of several genes associated with inflammation, T-cell activation and/or Treg function in pancreatic lymph node cells failed to reveal any differences associated with TCDD treatment. Taken together, the data suggest that AHR activation by TCDD-like ligands may represent a novel avenue for treatment of immune-mediated diseases.

scholarly journals Initiation of Autoimmune Diabetes by Developmentally Regulated Presentation of Islet Cell Antigens in the Pancreatic Lymph Nodes

1999 ◽  
Vol 189 (2) ◽  
pp. 331-339 ◽  
Author(s):  
Petter Höglund ◽  
Justine Mintern ◽  
Caroline Waltzinger ◽  
William Heath ◽  
Christophe Benoist ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Beta Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mimicry ◽  
Autoimmune Diabetes ◽  
Activated T Cells ◽  
Pancreatic Lymph Nodes

Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first “checkpoint” in diabetes progression.

scholarly journals The aryl hydrocarbon receptor is functionally upregulated early in the course of human T-cell activation

2014 ◽  
Vol 44 (5) ◽  
pp. 1330-1340 ◽  
Author(s):  
Laurie Prigent ◽  
Marc Robineau ◽  
Stéphane Jouneau ◽  
Claudie Morzadec ◽  
Laetitia Louarn ◽  
...  
Keyword(s):  
T Cell ◽  
Aryl Hydrocarbon Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Aryl Hydrocarbon ◽  
Human T Cell

Two lymph nodes draining the mouse liver are the preferential site of DC migration and T cell activation

2012 ◽  
Vol 57 (2) ◽  
pp. 352-358 ◽  
Author(s):  
Louise Barbier ◽  
Szun Szun Tay ◽  
Claire McGuffog ◽  
James A. Triccas ◽  
Geoffrey W. McCaughan ◽  
...  
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Mouse Liver ◽  
Cell Activation ◽  
Preferential Site

Experimental silicosis: a shift to a preferential IFN-γ-based Th1 response in thoracic lymph nodes

2000 ◽  
Vol 278 (6) ◽  
pp. L1221-L1230 ◽  
Author(s):  
Holger Garn ◽  
Anke Friedetzky ◽  
Andrea Kirchner ◽  
Ruth Jäger ◽  
Diethard Gemsa
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cell ◽  
Mrna Levels ◽  
Ifn Γ

In chronic silicosis, mechanisms leading to lymphocyte activation are still poorly understood, although it is well known that not only the lung but also the draining lymph nodes are affected. In the present study, we investigated T-cell activation by analysis of cytokine expression in the enlarged thoracic lymph nodes of rats 2 mo after an 8-day silica aerosol exposure. In the case of helper T cell (Th) type 1 cytokines, we found a significant increase in interferon (IFN)-γ mRNA expression, whereas interleukin (IL)-2 expression remained unchanged. In contrast, gene transcription for the Th2-type cytokines IL-4 and IL-10 was diminished. In addition, with use of an in vitro lymphocyte-macrophage coculture system, an enhanced IFN-γ and a reduced IL-10 release were shown with cells from silicotic animals. With regard to IFN-γ-inducing cytokines, we observed enhanced IL-12 mRNA levels in vivo, whereas IL-18 gene expression was slightly decreased. These data indicate that a persistent shift toward an IFN-γ-dominated type 1 (Th1/cytotoxic T cell type 1) T-cell reaction pattern occurred within the thoracic lymph nodes of silicotic animals. Thus a mutual activation of lymphocytes and macrophages may maintain the chronic inflammatory changes that characterize silicosis.

scholarly journals Superresolution imaging reveals nanometer- and micrometer-scale spatial distributions of T-cell receptors in lymph nodes

2016 ◽  
Vol 113 (26) ◽  
pp. 7201-7206 ◽  
Author(s):  
Ying S. Hu ◽  
Hu Cang ◽  
Björn F. Lillemeier
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Cell Receptors ◽  
Micrometer Scale

T cells become activated when T-cell receptors (TCRs) recognize agonist peptides bound to major histocompatibility complex molecules on antigen-presenting cells. T-cell activation critically relies on the spatiotemporal arrangements of TCRs on the plasma membrane. However, the molecular organizations of TCRs on lymph node-resident T cells have not yet been determined, owing to the diffraction limit of light. Here we visualized nanometer- and micrometer-scale TCR distributions in lymph nodes by light sheet direct stochastic optical reconstruction microscopy (dSTORM) and structured illumination microscopy (SIM). This dSTORM and SIM approach provides the first evidence, to our knowledge, of multiscale reorganization of TCRs during in vivo immune responses. We observed nanometer-scale plasma membrane domains, known as protein islands, on naïve T cells. These protein islands were enriched within micrometer-sized surface areas that we call territories. In vivo T-cell activation caused the TCR territories to contract, leading to the coalescence of protein islands and formation of stable TCR microclusters.

Su.13. Pancreatic Lymph Nodes of Prediabetic Nod Mice Preferentially Attract Dendritic Cells: Effects of Local Delivery of Il-4 By Lentivirally Transduced Dendritic Cells

2006 ◽  
Vol 119 ◽  
pp. S164
Author(s):  
Remi Creusot ◽  
Shahriar Yaghoubi ◽  
Demi Dang ◽  
Karine Breckpot ◽  
Kris Thielemans ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Nod Mice ◽  
Local Delivery ◽  
Pancreatic Lymph Nodes

Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX

2009 ◽  
Vol 419 (2) ◽  
pp. 419-425 ◽  
Author(s):  
Martina Takacova ◽  
Tereza Holotnakova ◽  
Jan Vondracek ◽  
Miroslav Machala ◽  
Katerina Pencikova ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Aryl Hydrocarbon Receptor ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Carbonic Anhydrase Ix ◽  
Independent Manner ◽  
Hypoxic Induction ◽  
Aryl Hydrocarbon ◽  
Ca Ix ◽  
Tcdd Treatment

Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1α and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1α competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.

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