Intrinsic roles of heat shock proteins in T-cell biology

热休克蛋白在 T 细胞生物学中的内在作用

• 批准号: RGPIN-2018-05272
• 负责人: vanGrevenynghe, Julien
• 金额: $ 2.26万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=667524
• 关键词: Intrinsic; roles; heat; shock; proteins

Heat shock proteins (HSPs) are the most conserved proteins present in all organisms. HSP expression is induced not only in hostile environments, but also under normal growth conditions where human cells have to handle the stress associated with activation, differentiation and the production of reactive oxygen species. Intracellular HSPs actively perform a number of "house-keeping" tasks through direct bindings including post-translational protein assembly and translocation, and cytoprotection. Several HSPs have been reported to play important roles in innate immunity illustrated by enhanced cell maturation and antigen presentation to specific T-lymphocytes. Our recent data clearly show higher intracellular expression of HSP70 and HSP60 in memory CD4 T-cells when compared to the naive population.****Although our basic knowledge regarding molecular events dictating T-cell immunity is increasing, the role of HSPs on the generation and maintenance of long-lasting memory cells has not been investigated before. Memory CD4 T-cell compartment plays a central role in our defense system by orchestrating the help to other populations, and producing an array of cytokines and soluble factors. Memory CD4 T-cells are known to be long-lasting populations, able to protect themselves against apoptosis and various insults. A few years ago, we demonstrated the critical involvement of the transcriptional factor FOXO3a in the survival of long-term memory CD4 T-populations. In my research program, our laboratory aims to unveil the contribution of the HSP family in adaptive immunity, and increase our incomplete knowledge of T-cell biology. In this proposal, we hypothesize that HSPs play a critical role in protecting long-term memory CD4 T-cells from apoptosis and in maintaining this population. We will focus on two intracellular HSPs, the HSP70 and HSP60. More specifically, by using an in vitro linear differentiation model and ex vivo highly purified cells, the objectives will be to understand the molecular mechanisms responsible for increased HSP expression, and their roles on T-cell integrity during the generation and maintenance of memory CD4 T-cells.****To conclude, the anticipated outcomes and the benefits to the research field and to Canada will be ensured in our research program by providing the evidence of a new molecular mechanism that plays a critical role on memory CD4 T-cell biology. In the long term run, my lab is also interested to assess HSP implication during the generation of T-cell immunological synapse following antigen stimulation, lineage commitment and plasticity, cell-cycling and cytokine production, as well as maturation and clonal selection process in thymus.******

热休克蛋白（HSPs）是所有生物体中最保守的蛋白质。HSP表达不仅在恶劣环境中被诱导，而且在正常生长条件下也被诱导，在正常生长条件下，人类细胞必须处理与活化、分化和活性氧产生相关的应激。细胞内的热休克蛋白通过直接结合，包括翻译后蛋白质组装和转运，以及细胞保护，积极地执行许多“管家”任务。已经报道了几种热休克蛋白在先天免疫中发挥重要作用，通过增强细胞成熟和抗原呈递给特异性T淋巴细胞来说明。我们最近的数据清楚地表明，与初始群体相比，记忆性CD4 T细胞中HSP 70和HSP 60的细胞内表达更高。虽然我们对决定T细胞免疫的分子事件的基本知识正在增加，但热休克蛋白对持久记忆细胞的产生和维持的作用以前尚未研究过。记忆性CD4 T细胞区室在我们的防御系统中起着核心作用，通过协调对其他群体的帮助，并产生一系列细胞因子和可溶性因子。已知记忆性CD4 T细胞是持久的群体，能够保护自己免受细胞凋亡和各种损伤。几年前，我们证明了转录因子FOXO3a在长期记忆CD4 T细胞群的生存中的重要作用。在我的研究计划中，我们的实验室旨在揭示HSP家族在适应性免疫中的贡献，并增加我们对T细胞生物学的不完整知识。在这个提议中，我们假设热休克蛋白在保护长期记忆CD4 T细胞免于凋亡和维持这一群体中起着关键作用。我们将集中在两个细胞内的热休克蛋白，热休克蛋白70和热休克蛋白60。更具体地说，通过使用体外线性分化模型和离体高度纯化的细胞，目的将是了解负责增加HSP表达的分子机制，以及它们在记忆性CD4 T细胞的产生和维持期间对T细胞完整性的作用。总之，我们的研究计划将通过提供对记忆CD4 T细胞生物学起关键作用的新分子机制的证据来确保预期的结果和对研究领域和加拿大的益处。从长远来看，我的实验室也有兴趣评估HSP在抗原刺激后T细胞免疫突触产生，谱系定型和可塑性，细胞周期和细胞因子产生以及胸腺成熟和克隆选择过程中的影响。