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

点击翻译按钮获取中文摘要

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.