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

描述（由申请人提供）：记忆T细胞在防止再次暴露于大多数病毒、寄生虫和细菌感染方面发挥重要作用。它们的产生和长期持续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。为了获得在记忆T细胞中独特表达的基因的无偏见的观点，我们开发了一个定义明确的CD 8 + T细胞受体转基因系统，结合Affyphase基因芯片来比较记忆与幼稚和效应群体。我们已经鉴定了在效应和记忆T细胞中上调的几种分子。其中之一，Fc-γ-受体IIb（Fc-γ RIIb）的缺失导致效应细胞数量增加，但功能性记忆细胞的总数减少。通过将Fc-γ RIIb缺陷杂交到CD 8 + T细胞转基因小鼠上，我们已经表明Fc-γ RIIb对记忆性CD 8 + T细胞发育的影响是T细胞内在的。 由于以前不知道Fc-γ RIIb在记忆T细胞分化中发挥直接作用，我们有兴趣发现这一新结果的分子基础。我们假设Fc-γ RIIb募集磷酸肌醇磷酸酶SHIP，并且这种募集用于抑制参与CD 8+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SHIP募集通过PIPS的去磷酸化导致Ca+通量的抑制，以及通过存活因子Akt的募集和通过p62 dok分子改变MAP激酶途径导致增殖的抑制。为此，我们提出确定1）Fc-γ RIIb是否通过调节IFN-γ和IL-7信号传导参与IL-7 R阳性效应CD 8 + T细胞的产生和收缩; 2）Fc-γ RIIb是否也是通过调节IL-7和IL-15信号传导进行记忆CD 8 + T细胞自我更新所需的; 3）T细胞上的Fc-γ RIIb表达是否改变SHIP及其下游介质PIPS、Akt和p62 dok的活化;和4）Fc-γ RIIb表达是否改变记忆性CD 8 + T细胞功能。希望更好地理解Fc-γ RIIb在记忆T细胞中的作用将最终导致更好地理解记忆细胞分化和功能所需的分子途径。

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.