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.

摘要 该建议的重点是热休克蛋白（HSP）在免疫反应的启动中的作用。 30多年来的研究表明，6种热休克蛋白，即gp 96、hsp 70、hsp 90、钙网蛋白、hsp 110 和grp 170，在细胞外环境中，引发对它们陪伴的抗原特异性的T细胞应答。许多 关于这些热休克蛋白如何引发免疫反应的机制方面仍然未知，即使 热休克蛋白目前正在探索用于癌症和传染病患者的临床免疫治疗。一 在这方面的主要进展是我们鉴定了CD 91作为HSP的细胞表面受体。CD 91服务 作为gp 96、hsp 90、hsp 70和钙网蛋白的内吞和信号受体。最近，我们和其他人 观察到gp 96、hsp 70和钙网蛋白引起的免疫结果的差异， 都与受体CD 91相互作用并依赖于受体CD 91。由CD 91下游转导的信号似乎 当每个HSP与受体结合时，它们是不同的，导致共同刺激的差异模式。这 包括细胞因子的差异模式和由抗原引起的共刺激分子的表达 提呈细胞（APC）。其中，HSP可以引发Th 1、Th 2、Treg或Th 17应答。因此，我们制定了 根据总体假设;“细胞外环境中的HSP各自与APC上的CD 91相互作用， 独特的方式来激活不同的途径，包括炎性小体共刺激”。第一个目标 该提案研究了gp 96/hsp 90、hsp 70或钙网蛋白与各种配体结合结构域的相互作用， 在APC上表达的CD 91。热休克蛋白与CD 91的相互作用是必要的，既内化的， HSP-肽复合物和用于APC内的信号转导。由于几乎没有明显的结构性 热休克蛋白之间的同源性，缺乏共同的相互作用模块，每个结构的相互作用， HSP与CD 91必须是独特的，启动信号级联反应和个体细胞因子模式。我们将 检查CD 91上每个相应HSP的结合结构域。为了实现这一目标，我们将 鉴定与CD 91的磷酸化胞质结构域相关的接头蛋白， 每个HSP配体，提供了一个洞察不同的信号通路，启动。第二个目标， 我们关注HSP-CD 91相互作用的细胞结果，特别是细胞因子的释放和相关的 佐剂性IL-1是一种通常从HSP刺激的APC释放的细胞因子。我们提出 热休克蛋白能够激活炎性小体的成分，已知这是IL-1分泌所必需的。 release.该提案的结果预计将在很大程度上为下一代基于HSP的 癌症和传染病的疫苗正在研发中。