Examination of inflammatory transcripts during a transfer model of type I diabetes.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE26147 | GEO | 2011/02/16
SECONDARY ACCESSION(S): PRJNA135303
REPOSITORIES: GEO
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Project description:In an accompanying paper we found specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intra-islet dendritic cells bearing the β-cell-peptide-MHC complex. Here we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. VCAM-1 expression was notable in blood vessels and so was ICAM-1. ICAM-1 was also found on β-cells. These expression changes induced the entry of non-specific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of non-specific T cells required a chemokine response and VCAM-1 expression by the islets. Interferon-gamma was important for the early gene expression changes in the islets. By microarray analysis we detected up-regulation of a group of interferon-inducible genes as early as 8 hours post T cell transfer. These studies provide a baseline to examine the development of therapeutics that can modulate islet localization of diabetogenic T cells to control this autoimmune disease. 20 total samples
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Project description:The exit of antigen-presenting cells (APC) and lymphocytes from inflamed skin to afferent lymph is vital for the initiation and maintenance of dermal immune responses. How such exit is achieved and how cells transmigrate the distinct endothelium of lymphatic vessels is however unknown. Here we show that inflammatory cytokines trigger activation of dermal lymphatic endothelial cells (LEC) leading to expression of the key leukocyte adhesion receptors ICAM-1, VCAM-1 and E-selectin, as well as a discrete panel of chemokines and other potential regulators of leukocyte transmigration. Furthermore, we show that both ICAM-1 and VCAM-1 are induced in the dermal lymphatic vessels of mice exposed to skin contact hypersensitivity where they mediate lymph node trafficking of DC via afferent lymphatics. Lastly, we show that TNF_-stimulates both DC adhesion and transmigration of dermal LEC monolayers in vitro and that the process is efficiently inhibited by ICAM-1 and VCAM-1 adhesion-blocking mAbs. These results reveal a CAM-mediated mechanism for recruiting leukocytes to the lymph nodes in inflammation and highlight the process of lymphatic transmigration as a potential new target for anti-inflammatory therapy. Experiment Overall Design: Global gene expression profile of normal dermal lymphatic endothelial cells cultured in media alone (no TNF) compared to that of normal dermal lymphatic endothelial cells stimulated with TNFalpha, 1 ng/ml for 48h.Triplicate biological samples were analyzed from human lymphatic endothelial cells (3 x controls; 3 x TNF treated) and a single sample analyzed from mouse lymphatic endothelial cells (1 x controls; 1 x TNF treated).
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