Unknown,Transcriptomics,Genomics,Proteomics

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Mannose receptor-induced T cell tolerance via interaction with CD45 and up-regulation of CTLA-4

ABSTRACT: The MR is an endocytic receptor, which plays an important role in serum homeostasis and antigen presentation. In this study, we firstly describe an important role of the MR as a direct regulator of CD8+ T cell activity. We could demonstrate that the presence of the MR on DCs impaired the cytotoxicity of activated CD8+ T cells both in vitro and in vivo. This regulatory effect was mediated by a direct interaction of the MR with CD45 on the T cells surface, which abolished CD45 activity. MR-mediated suppression of CD45 resulted in the up-regulation of the inhibitory molecule CTLA-4, which in turn was responsible for the reduced T cell activity. MR-mediated inactivation of CD45, up-regulation of CTLA-4 and T cell inactivation could be circumvented by increased signaling via CD28, which was achieved by DC maturation. These implications point out an important role of the MR in maintaining the balance between tolerance and immunity and might have pivotal implications for the development of vaccination strategies aimed at dampening adaptive immunity. DesTCR T cells were incubated with MR-deficient DCs in the presence of FcMR or isotype controls for the indicated time points. Afterwards, CD8+ T cells were isolated by cell sorting (FACSAria), and immediately lysed in Trizol (Invitrogen) before storage at -80Â°C for RNA isolation.

ORGANISM(S): Mus musculus

SUBMITTER: Joachim Schultze

PROVIDER: E-GEOD-45805 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Elevated plasma levels of High Density Lipoprotein (HDL) are associated with decreased risk of cardiovascular disease (CVD). The protective role of HDL in atherosclerosis has been attributed primarily to its ability to remove excess cholesterol from lipid-laden macrophages (foam cells) within the arterial walls. However, clinical trials that raise HDL cholesterol levels have failed to show a benefit casting doubts on our basic understanding of HDL function. Atherosclerosis is a chronic inflammatory condition underlying CVD and driven in part by the recognition of metabolic danger signals by innate immune receptors on macrophages. A potential feature that could contribute to HDL’s protective effects in CVD could be HDL's anti-inflammatory nature, such as its ability to reduce endothelial cell activation. However, the molecular mechanisms by which HDL reduces inflammatory macrophage responses remain poorly understood and difficult to separate from its cholesterol depleting activity. Here we show that HDL protects against Toll like receptor (TLR)-induced inflammation both in vivo and in vitro under normocholesteremic conditions by suppressing the transcription of inflammatory cytokines in a manner independent of its ability to remove cellular cholesterol. We identify Activating Transcription Factor 3 (ATF3), a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a HDL-inducible regulator of macrophage activation. HDL’s ability to down modulate TLR responses was severely compromised in ATF3-deficient cells demonstrating that ATF3 mediates HDL's anti-inflammatory effects and may explain the broad anti-inflammatory functions of HDL. Bone marrow-derived macrophages (BMDMs) were obtained by culturing bone marrow cells from 6 to 8 week old wildtype C57BL/6 mice in DMEM supplemented with 10% FCS, 10 mg ml-1 Ciprobay-500 and 40 ng ml-1 M-CSF (R & D Systems). BMDMs of wt mice were pretreated for 6 h with HDL (2 mg ml-1 ) then stimulated with CpG (100 nM) for 4 h. Further wild type or Atf3-deficient BMDMs were pretreated with 2 mg ml-1 HDL for 6 h and subsequently stimulated with CpG (100 nM) or P3C (50 ng ml-1) for 4 h. For carotid artery injury approximately 12-week old male WT and Atf3-deficient mice were anesthetized with i.p. injection of 150 mg/kg ketaminehydrochloride (Ketanest, Pharmacia) and 0.1 mg/kg xylazinehydrochloride (Rompun 2%, Bayer). A small incision from the cranial apex of the sternum to just below the mandible was made. After careful preparation of an approximately 6 mm long segment proximal of the bifurcation, the common carotid artery was electrically denuded. A 4 mm long lesion was made by applying two serial 5 second bursts of 2 Watt using 2 mm wide forceps. The skin was then sutured and the mice allowed to recover in individual cages before returning to their littermates. Three hours later the mice received a single 200 ?l i.v. injection of 20 mg/kg HDL or PBS.

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Mannose receptor-induced T cell tolerance via interaction with CD45 and up-regulation of CTLA-4

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