Heat shock protein gp96 and Treg responses

热休克蛋白 gp96 和 Treg 反应

基本信息

批准号：
9606843
负责人：
Robert J Binder
金额：
$ 19.43万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-18 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9606843
关键词：
Address Antigen Presentation Antigen-Presenting Cells Area Autoimmune Diseases Autoimmunity Biological Assay Cancer Model Cell physiology Cells ChIP-seq Clinical Communicable Diseases Cross Presentation DNA Methylation DNA Modification Methylases Dendritic Cells Development Disease Effector Cell Endocytosis Environment Gene Expression Gene Expression Profile Gene Expression Regulation Genetic Genomic DNA Heat shock proteins Immune response Immunologic Monitoring Immunosuppression Immunotherapy In Situ Infection Inflammation Investigation Knockout Mice Label Laboratories Malignant Neoplasms Mediating Methylation Modification Molecular Molecular Chaperones Mus Pathway interactions Peptides Phenotype Play Population Protein Analysis Publishing Regulatory Element Regulatory T-Lymphocyte Role Shapes Signal Transduction Sterility T cell response T-Lymphocyte Therapeutic Up-Regulation base cancer immunotherapy defined contribution design direct application extracellular genetic signature genome wide methylation genome-wide analysis immunogenic in vivo infectious disease model methylation pattern mouse model novel programs receptor response transcription factor REST tumor

项目摘要

Abstract The heat shock protein (HSP) gp96 is immunogenic. Depending on which antigen presenting cell (APC) is targeted by gp96 in the extracellular environment, these immune responses can be opposingly of the Th1 or Treg type. These immune responses have been harnessed for the immunotherapy of cancer and infectious disease or autoimmune disease respectively. We have shown that the gp96 receptor, CD91, is expressed by conventional dendritic cell (cDCs) which allows for cross-presentation of the antigens chaperoned by gp96 and for provision of co-stimulation for Th1 responses. We have recently uncovered CD91 expression on plasmacytoid dendritic cells (pDCs). There is currently no information on how pDCs influence gp96-mediated immune responses and specifically, how Treg responses are modulated. Our hypothesis is that engagement of pDCs by gp96 via CD91 leads to intracellular signaling and upregulation of molecules associated with priming and stabilization of Treg function. Our studies here explore how gp96 engages the various APC populations in situ, the intracellular signaling with pDCs, and the phenotype of gp96-activated pDCs in the context of priming Tregs and enhancement of their function. This pathway has consequences not only for tumor development and infection but in autoimmunity, and in immunotherapy of these diseases.

抽象的热休克蛋白（HSP）GP96具有免疫原性。取决于哪个抗原呈现细胞（APC）为这些免疫反应在细胞外环境中针对GP96，可以与TH1或 Treg类型。这些免疫反应已被利用用于癌症和感染性的免疫疗法疾病或自身免疫性疾病。我们已经表明，GP96受体CD91由常规的树突状细胞（CDC），允许通过GP96和GP96和抗原交叉呈递用于为TH1响应提供共同刺激。我们最近在浆细胞样树突状细胞（PDC）。目前尚无有关PDC如何影响GP96介导的信息免疫反应，具体来说，如何调节Treg响应。我们的假设是参与 GP96通过CD91的PDC导致细胞内信号传导和与启动相关的分子的上调和Treg功能的稳定。我们在这里的研究探讨了GP96如何参与各种APC人群在启动的背景下 Tregs和它们功能的增强。该途径不仅对肿瘤发展和感染但自身免疫性以及这些疾病的免疫疗法。