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. PUBLIC HEALTH RELEVANCE: Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. Nevertheless, the detailed underlying mechanisms regulating the generation and persistence of long-lived immunological memory remain largely undefined. Our proposal aims to build on our recent novel findings that strongly implicate a requirement for catabolic energy generating processes in the establishment of immunological memory and seeks to provide proof of principle that existing FDA approved drugs that are currently widely prescribed for metabolic and other disorders can be used to great effect to improve vaccine efficacy.