Intrinsic roles of heat shock proteins in T-cell biology

热休克蛋白(HSPs)是生物体中存在的最保守的蛋白质。热休克蛋白的表达不仅在恶劣的环境中被诱导，而且在正常的生长条件下，人类细胞必须处理与激活、分化和产生活性氧有关的压力。细胞内的热休克蛋白通过直接结合主动地执行许多“看家”任务，包括翻译后蛋白质组装和转位，以及细胞保护。据报道，一些热休克蛋白在先天免疫中发挥重要作用，表现为增强细胞成熟和将抗原递呈给特定的T淋巴细胞。我们最近的数据清楚地表明，与幼稚人群相比，记忆CD4T细胞内HSP70和HSP60的表达更高。*尽管我们关于决定T细胞免疫的分子事件的基本知识正在增加，但以前还没有研究过HSPs在长期记忆细胞的产生和维持中的作用。记忆CD4T细胞室在我们的防御系统中发挥着核心作用，它通过协调对其他人群的帮助，并产生一系列细胞因子和可溶性因子。众所周知，记忆CD4T细胞是一种持久的群体，能够保护自己免受凋亡和各种侮辱。几年前，我们展示了转录因子FOXO3a在长期记忆的CD4T细胞群生存中的关键作用。在我的研究计划中，我们的实验室旨在揭示热休克蛋白家族在适应性免疫中的贡献，并增加我们对T细胞生物学的不完全知识。在这项建议中，我们假设热休克蛋白在保护长期记忆的CD4T细胞免受凋亡和维持这一群体方面发挥关键作用。我们将关注两个细胞内的HSP70和HSP60。更具体地说，通过使用体外线性分化模型和体外高纯度细胞，目标将是了解导致HSP表达增加的分子机制，以及它们在记忆CD4 T细胞产生和维持过程中对T细胞完整性的作用。*总结，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的分子机制的证据，确保预期的结果和对研究领域和加拿大的好处。从长远来看，我的实验室也有兴趣评估HSP在胸腺中抗原刺激后T细胞免疫突触的产生、谱系承诺和可塑性、细胞周期和细胞因子的产生以及成熟和克隆选择过程中的作用。

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.******