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

描述(由申请人提供)：记忆T细胞在保护免受大多数病毒、寄生虫和细菌感染的再次暴露方面发挥着重要作用。它们的产生和长期持久性是成功接种疫苗所必需的，无论是针对常见的儿童感染还是潜在的生物威胁。为了公正地了解记忆T细胞中独特表达的基因，我们开发了一个定义明确的CD8+T细胞受体转基因系统，并结合Affymetrix GeneChips来比较记忆与幼稚和效应群体。我们已经确定了几个在效应性和记忆性T细胞中上调的分子。Fc-Gamma受体Lib(Fc-GammaR11b)的缺失导致效应细胞数量的增加，但功能记忆细胞的总数减少。通过将Fc-GammaR11b缺陷与CD8+T细胞转基因小鼠杂交，我们发现Fc-GammaR11b对记忆性CD8+T细胞发育的影响是T细胞固有的。 由于Fc-GammaR11b在记忆T细胞分化中的直接作用尚不为人所知，我们有兴趣发现这一新结果的分子基础。我们假设Fc-GammaR11b招募了磷酸肌醇磷酸酶船，这种招募作用是为了抑制参与CD8+记忆细胞生成和维持的阳性TCR和细胞因子信号。我们进一步假设，SHIP重启通过PIPs去磷酸化抑制Ca~+流，并通过p62dok分子重启生存因子Akt和改变MAP-Kinase通路而抑制细胞增殖。为此，我们建议确定1)Fc-GammaRllb是否通过调节干扰素-γ和IL-7信号参与了IL-7R阳性效应CD8+T细胞的产生和收缩；2)Fc-GammaRllb是否也是记忆CD8+T细胞通过调节IL-7和IL-15信号而自我更新所必需的；3)T细胞上Fc-GammaRllb的表达是否改变了SHIP及其下游介质PiP、Akt和p62dok的激活；以及4)Fc-GammaRllb的表达是否改变了记忆CD8+T细胞的功能。人们希望，对Fc-GammaRllb在记忆T细胞中作用的更好理解将最终导致对记忆细胞分化和功能所需的分子途径的更好理解。

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.