Heat shock proteins and modulation of immune responses

热休克蛋白和免疫反应的调节

• 批准号: 9307761
• 负责人: Robert J Binder
• 金额: $ 16.81万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307761
• 关键词: Adaptor Signaling Protein; Adjuvanticity; Agonist; Alpha Cell; Antigen-Presenting Cells; Antigens; Attention; Binding; Binding Proteins; CASP1 gene; Cancer Vaccines; Cell Surface Receptors; Cell physiology; Clinic; Clinical; Communicable Diseases; Complex; Cytoplasmic Tail; Data; Environment; Event; Goals; Heat shock proteins; Immune; Immune response; Immunity; Immunobiology; Immunologics; Immunotherapy; Individual; Infection; Inflammasome; Interleukin-1; Interleukin-1 alpha; Knowledge; Laboratories; Lead; Ligand Binding Domain; Ligands; Light; Malignant Neoplasms; Mediating; Molecular; Molecular Chaperones; Outcome; Pathway interactions; Patients; Pattern; Peptides; Phosphorylation; Process; Production; Receptor Signaling; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; T cell response; Vaccines; base; calreticulin; cancer immunotherapy; cytokine; extracellular; immunogenic; immunoregulation; improved; insight; next generation; pathogen; receptor; response; tumor

Abstract This proposal focuses on the role of the heat shock proteins (HSPs) in the initiation of immune responses. Evidence gathered over three decades shows that six HSPs namely gp96, hsp70, hsp90, calreticulin, hsp110 and grp170, in the extracellular environment, prime T cell responses specific to antigens they chaperone. Many aspects regarding the mechanism of how these HSPs prime immune responses remain unknown, even though HSPs are now being explored in clinical immunotherapy of patients with cancer and infectious disease. A major advance in this regard was our identification of CD91 as a cell surface receptor for HSPs. CD91 serves as an endocytic and signaling receptor for gp96, hsp90, hsp70 and calreticulin. Recently, we and others have observed differences in the immune outcomes elicited by gp96, hsp70 and calreticulin despite the fact that they all interact with and are dependent on the receptor CD91. Signals transduced by CD91 downstream appear to be different when each HSP engages the receptor, leading to differential patterns of co-stimulation. This includes differential patterns of cytokines and expression of co-stimulatory molecules elicited by the antigen presenting cell (APC). Therein, HSPs can prime Th1, Th2, Treg or Th17 responses. We thus formulate the following overall hypothesis; “HSPs in the extracellular environment each interact with CD91 on APCs in a unique way to activate distinct pathways including the inflammasome for co-stimulation”. The first aim of the proposal examines the interaction of gp96/hsp90, hsp70, or calreticulin with various ligand binding domains of CD91 expressed on APCs. The interaction of HSPs with CD91 is necessary for both the internalization of the HSP-peptide complex and for transduction of signals within the APC. Since there is little apparent structural homology between the HSPs, and a lack of common interacting modules, the structural interaction of each HSP with CD91 must be unique, initiating signaling cascades and individual cytokine patterns. We shall examine the binding domains on CD91 for each of the respective HSPs. In an extension of this aim, we shall identify adaptor proteins that associate with the phosphorylated cytoplasmic domain of CD91 with respect to each HSP ligand, providing an insight into the different signaling pathways that are initiated. In the second aim, we focus on cellular outcomes of the HSP-CD91 interaction, specifically cytokine release and related adjuvanticity. IL-1 a cytokine that is commonly released from HSP-stimulated APCs is explored. We propose that HSPs are capable of activating components of the inflammasome, known to be necessary for IL-1 release. Results from this proposal are expected to inform heavily on the next generation of HSP-based vaccines for cancer and infectious disease being developed.

抽象的 该提案的重点是热休克蛋白（HSP）在免疫复杂倡议中的作用。 在三十年中收集的证据表明，六个HSP，即GP96，HSP70，HSP90，钙网蛋白，HSP110 和GRP170，在细胞外环境中，对伴侣抗原特有的主要T细胞反应。许多 关于这些HSP的主要免疫反应如何仍然未知的机制，即使 HSP现在正在癌症和传染病患者的临床免疫疗法中探索。一个 这方面的主要进步是我们将CD91鉴定为HSP的细胞表面受体。 CD91服务 作为GP96，HSP90，HSP70和钙网蛋白的内吞和信号受体。最近，我们和其他人有 观察到GP96，HSP70和钙网蛋白使命引起的免疫结局的差异 所有与接收器CD91相互作用并取决于。由CD91下游外观翻译的信号为 当每个HSP接合接收器时，请有所不同，从而导致共同刺激的差异模式。这 包括细胞因子的差异模式和抗原引起的共刺激分子的表达 呈现细胞（APC）。在其中，HSP可以启用Th1，Th2，Treg或Th17响应。因此，我们制定了 遵循总体假设； “细胞外环境中的HSP在A中的APC上与CD91相互作用 激活不同途径的独特方法，包括共同刺激的炎症组”。 提案检查GP96/HSP90，HSP70或Calleticulin与各种配体结合域的相互作用 CD91在APC上表示。 HSP与CD91的相互作用对于两者的内在化都是必要的 HSP肽复合物和APC中信号的翻译。由于几乎没有明显的结构 HSP之间的同源性和缺乏共同的相互作用模块，每个模块的结构相互作用 带有CD91的HSP必须是独特的，启动的信号级联和单个细胞因子模式。我们将 检查每个相应的HSP上CD91上的结合域。为了扩展此目标，我们将 鉴定与CD91的磷酸化细胞质结构域相关的衔接蛋白 每种HSP配体，都可以洞悉启动的不同信号通路。在第二个目标中 我们专注于HSP-CD91相互作用的细胞结局，特别是细胞因子释放和相关 辅助性。探索了通常从HSP刺激的APC中释放的细胞因子IL-1。我们建议 HSP能够激活炎性体的成分，这是IL-1所必需的 发布。预计该提案的结果将大大了解下一代基于HSP 开发了用于癌症和传染病的疫苗。