Metabolic Regulation of CD8 T Cell Memory Development

描述(由申请人提供)：免疫记忆是接种疫苗的基础，疫苗接种可能是当今最重要的公共卫生工具。CD8T细胞在抵抗细胞内病原体感染的免疫中起着至关重要的作用。在刺激下，这些T细胞经历了一个发育程序，其特征是具有不同的阶段，首先是抗原特异性效应T细胞群体的扩张，然后是收缩，然后是持续存在的长期记忆T细胞，介导对再次感染的免疫。记忆性CD8 T细胞的产生和维持机制尚不清楚。以前我们证明了T细胞中缺乏Traf6(一种TNFR和IL-1/TLR家族适配蛋白)的小鼠可以安装效应CD8T细胞对感染做出反应，但不能建立记忆CD8T细胞。我们的实验表明，这种CD8T细胞固有的记忆发育失败与Traf6缺陷的CD8T细胞无法启动线粒体脂肪酸氧化密切相关，线粒体脂肪酸氧化是一种脂质分解代谢途径，为TCA循环提供燃料。基于我们的观察和一组支持性的初步数据，我们假设能量产生的分解代谢过程对于感染后记忆CD8 T细胞的发育是必不可少的，Traf6在调节这一过程中起着关键作用。我们将通过以下具体目标来验证这一假说：1)确定脂肪酸代谢如何调节记忆CD8 T细胞的发育；2)确定Traf6对记忆CD8 T细胞发育的依赖调节的程度；以及3)建立对CD8 T细胞代谢的药物操纵可以是治疗的。这些研究的长期目标是促进针对传染病的免疫疗法的发展。

DESCRIPTION (provided by applicant): Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. CD8 T cells play a crucial role in immunity to infections with intracellular pathogens. Upon stimulation, these T cells undergo a developmental program characterized by distinct phases encompassing first the expansion, and then contraction, of antigen-specific effector T cell populations, followed by the persistence of long-lived memory T cells that mediate immunity to re-infection. The mechanisms underlying the generation and maintenance of memory CD8 T cells remain unclear. Previously we demonstrated that mice lacking Traf6 (a TNFR and IL-1/TLR family adapter protein) in T cells mount effector CD8 T cell responses to infection, but are unable to establish memory CD8 T cells. Our experiments revealed that this CD8 T cell intrinsic failure of memory development was tightly linked to the inability of Traf6-deficient CD8 T cells to initiate mitochondrial fatty acid oxidation, a pathway of lipid catabolism that fuels the TCA cycle. Based on our observations, and a panel of supportive preliminary data, we hypothesize that catabolic processes of energy generation are essential for the development of memory CD8 T cells after infection and that Traf6 plays a key role regulating this process. We will test this hypothesis through the following specific aims: 1) Determine how fatty acid metabolism regulates memory CD8 T cell development; 2) Determine the extent of Traf6-dependent regulation of memory CD8 T cell development; and 3) Establish that pharmacological manipulation of CD8 T cell metabolism can be therapeutic. The long-term goal of these studies is to facilitate the development of immunotherapies against infectious diseases.