Metabolic Regulation of CD8 T Cell Memory Development

描述（由申请人提供）：免疫记忆是疫苗接种的基础，这可能是当今最重要的公共卫生工具。CD8 T细胞在细胞内病原体感染的免疫中起着至关重要的作用。在受到刺激后，这些T细胞经历了一个发育过程，其特征是不同的阶段，首先是抗原特异性效应T细胞群的扩张，然后是收缩，随后是长期记忆T细胞的持续存在，介导对再感染的免疫。记忆性CD8 T细胞产生和维持的机制尚不清楚。先前我们证明了缺乏Traf6（一种TNFR和IL-1/TLR家族适配蛋白）的小鼠在T细胞中对感染产生效应CD8 T细胞反应，但不能建立记忆CD8 T细胞。我们的实验显示，这种CD8 T细胞记忆发育的内在失败与traf6缺陷CD8 T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。根据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感染后记忆性CD8 T细胞的发育至关重要，而Traf6在调节这一过程中起关键作用。我们将通过以下具体目标来验证这一假设：1)确定脂肪酸代谢如何调节记忆性CD8 T细胞的发育；2)确定traf6依赖性调节记忆性CD8 T细胞发育的程度；3)建立CD8 T细胞代谢的药理学操作可以治疗。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.