The Role of FcGamma-Rllb in Memory T cell self-renewal

FcGamma-Rllb 在记忆 T 细胞自我更新中的作用

• 批准号: 6982702
• 负责人: CHANCE MARION JOHN LUCKEY
• 金额: $ 11.77万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6982702
• 关键词: T cell receptor; antibody receptor; calcium flux; cell differentiation; cell population study; cellular immunity; cytokine receptors; cytotoxic T lymphocyte; enzyme activity; gene expression; genetically modified animals; immunogenetics; immunologic memory; inositol phosphates; interferon gamma; interleukin 15; interleukin 7; laboratory mouse; lymphocyte proliferation; phosphatidylinositols; phosphoprotein phosphatase; phosphorylation; receptor expression; vaccinia virus; virus diseases

DESCRIPTION (provided by applicant): Memory T cells play an essential role in protection from re-exposure to most viral, parasitic, and bacterial infections. Their generation and long-term persistence is required for successful vaccination, whether against common childhood infections or potential biological threats. In order to gain an unbiased view of the genes uniquely expressed in memory T cells, we developed a well-defined CD8+ T cell receptor transgenic system combined with Affymetrix GeneChips to compare memory with naive and effector populations. We have identified several molecules that are up regulated in effector and memory T cells. The absence of one of these, Fc-gamma-Receptor lIb (Fc-gammaRllb), results in an increase in effector cells numbers but a decrease in the total number of functional memory cells. By crossing the Fc-gammaRllb defect onto a CD8+ T cell transgenic mouse, we have shown that the effect of Fc-gammaRllb on the development of memory CD8+ T cells is T cell intrinsic. As Fc-gammaRllb was not previously known to play a direct role in memory T cell differentiation, we are interested in discovering the molecular basis for this novel result. We hypothesize that Fc-gammaRllb recruits the phosphoinositol phosphatase SHIP, and that this recruitment serves to dampen the positive TCR and cytokine signals involved in CD8+ memory cell generation and maintenance. We further hypothesize that SHIP recruitment leads to inhibition of Ca+ flux via dephosphorylation of PIPS as well as inhibition of proliferation via recruitment of the survival factor Akt and altering the MAP Kinase pathway via the p62dok molecule. Towards that end, we propose to determine 1) whether Fc-gammaRllb is involved in the generation and contraction of IL-7R positive effector CD8+ T cells though modulation of IFN-gamma and IL-7 signaling; 2) if Fc-gammaRllb is also required for memory CD8+ T cell self-renewal through modulation of IL-7 and IL-15 signaling; 3) whether Fc-gammaRllb expression on T cells alters the activation of SHIP and its downstream mediators PIPS, Akt, and p62dok; and 4) whether Fc-gammaRllb expression alters memory CD8+ T cell function. It is hoped that a better understanding of the role of Fc-gammaRllb in memory T cells will ultimately lead to a better understanding of the molecular pathways required for memory cell differentiation and function.

描述（由申请人提供）：记忆T细胞在防止重新暴露于大多数病毒，寄生和细菌感染中起着至关重要的作用。成功的疫苗接种是必需的，无论是针对儿童常见感染还是潜在的生物威胁，都需要长期持久性。为了获得在记忆T细胞中唯一表达的基因的公正视图，我们开发了一个定义明确的CD8+ T细胞受体转基因系统，结合了Affymetrix Genechips，以将记忆与天真和效应子种群进行比较。我们已经确定了几个在效应子和记忆T细胞中调节的分子。其中一种缺少FC-GAMMA受体LIB（FC-GAMMARLLB）导致效应细胞数量增加，但功能记忆细胞总数减少。通过将FC-GammarllB缺陷跨到CD8+ T细胞转基因小鼠上，我们表明FC-GammarllB对内存CD8+ T细胞发展的影响是T细胞的固有。 由于以前尚不知道FC-GammarllB在记忆T细胞分化中起着直接作用，因此我们有兴趣发现这种新结果的分子基础。我们假设FC-GammarllB募集了磷酸肌醇磷酸酶船，并且该募集会抑制参与CD8+记忆细胞产生和维持的阳性TCR和细胞因子信号。我们进一步假设，船舶募集会导致通过PIP的去磷酸化来抑制Ca+通量，并通过募集生存因子AKT抑制增殖，并通过p62dok分子改变MAP激酶途径。为此，我们建议确定1）FC-GammarllB是否参与IL-7R阳性效应子CD8+ T细胞的产生和收缩，但通过调节IFN-GAMMA和IL-7信号传导； 2）如果还需要通过调节IL-7和IL-15信号传导来使记忆CD8+ T细胞自我更新也需要FC-GammarllB； 3）T细胞上的FC-Gammarllb表达是否会改变船舶的激活及其下游介体PIPS，AKT和P62DOK； 4）FC-GammarllB表达是否会改变内存CD8+ T细胞功能。希望更好地理解FC-GammarllB在记忆T细胞中的作用，最终将更好地理解记忆细胞分化和功能所需的分子途径。