Aging effect on PLD Signaling in T Cells

描述（由申请方提供）：老年人群免疫应答降低导致感染频率增加和缺乏疫苗接种应答。老年人对新型病毒和生物恐怖主义分子的脆弱性提高了理解免疫反应被衰老抑制的机制的重要性。我们以前的研究表明，从年轻小鼠骨髓干细胞成熟的T细胞在老年宿主小鼠中的反应性严重受损。这些T细胞重演了正常老化小鼠T细胞的表型。另一方面，当在年轻小鼠环境中分化时，来自老年小鼠骨髓干细胞的T细胞与来自年轻小鼠骨髓干细胞的T细胞一样对刺激有应答。提示老龄小鼠体内环境对T细胞免疫功能的损害起着重要作用。在老年小鼠中，也有报道称Foxp3+调节性T细胞（TCRs）的频率高于年轻小鼠。T细胞不仅对预防自身免疫性疾病很重要，而且在各种病原体引起的慢性感染中也起着关键作用。因此，调节性T细胞的增加可能是导致老年人群免疫应答降低的一个因素。我们最近已经证明，在T细胞中磷脂酶D（PLD）信号的抑制导致选择性富集的TCLs。PLD信号传导的抑制导致T细胞对抗原应答的严重抑制。此外，PLD信号已被证明是敏感的膜脂质组成。基于这些数据，我们假设老年人群中的T细胞应答通过PLD信号传导的减少而受损。这种减少可以影响效应T细胞的反应性，并改变Tcl3和非Tcl3之间的平衡，使Tcl3占优势。我们将确定PLD信号抑制是否由老年小鼠的内部环境施加。该项目将有助于了解衰老损害免疫系统功能的机制。这项研究的主要目的是确定衰老对一组称为调节性T细胞和其他淋巴细胞之间平衡的影响。调节性T细胞在预防自身免疫性疾病中发挥关键作用，但也抑制对感染和癌症的免疫力。提示老年小鼠内环境可能增加了调节细胞的频率。我们将在这项研究中确定导致老年人免疫细胞失衡的因素。

DESCRIPTION (provided by applicant): Reduced immune response in elderly population contributes to increased frequency of infection and lack of responses against vaccination. Vulnerability of the elderly to novel type of virus and agents of bioterrorism raises significance of understanding the mechanism by which immune response is suppressed by aging. Our previous study showed that T cells that mature from young mouse bone marrow stem cells in the aged host mice have severe impairment in their responsiveness. These T cells recapitulated phenotypes of normally aged mouse T cells. On the other hand, T cells derived from aged mouse bone marrow stem cells, when differentiated in the young mouse environment, were responsive to stimuli as well T cells derived from young mouse bone marrow stem cells. The data suggested that the internal environment of aged mouse plays a critical role in impairment of T cell responses. In aged mice, it was also reported that the frequency of Foxp3+ regulatory T cells (Tregs) is higher than in young mice. Tregs are not only important for preventing autoimmune disease but also play critical roles in establishment of chronic infection by various agents. Thus, increase of regulatory T cells may be a factor that causes reduced immune responses in the aged population. We have recently demonstrated that inhibition of phospholipase D (PLD) signaling in T cells causes selective enrichment of Tregs. Inhibition of PLD signaling causes severe inhibition of antigen responses by T cells. Moreover, PLD signaling has been shown to be sensitive to membrane lipid composition. Based on these data, we hypothesize that T cell responses in aged population are impaired by reduction of PLD signaling. Such reduction can affect responsiveness of effector T cells and change the balance between Tregs and non-Tregs toward the dominance by Tregs. We will determine if PLD signal inhibition is imposed by the internal environment of aged mice. This project will help understanding the mechanism by which aging impairs the function of the immune system. The main object of this research is to determine the effect of aging on the balance between a group of lymphocytes called regulatory T cells and others. Regulatory T cells play pivotal roles in prevention of autoimmune disease but also suppress immunity against infection and cancer. Our data show that the internal environment of aged mouse may increase the frequency of regulatory cells. We will determine the factor that causes such imbalance of immune cells in the elderly in this study.