Metabolic Regulation of CD8 T Cell Memory Development

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。CD 8 T细胞在对细胞内病原体感染的免疫中起着至关重要的作用。在刺激后，这些T细胞经历发育程序，其特征在于不同的阶段，包括抗原特异性效应T细胞群体的首先扩增，然后收缩，然后是介导对再感染的免疫力的长寿命记忆T细胞的持续存在。记忆性CD 8 T细胞的产生和维持机制尚不清楚。先前我们证明了T细胞中缺乏Traf 6（TNFR和IL-1/TLR家族衔接蛋白）的小鼠对感染产生效应CD 8 T细胞应答，但不能建立记忆CD 8 T细胞。我们的实验表明，这种CD 8 T细胞记忆发育的内在失败与Traf 6缺陷的CD 8 T细胞无法启动线粒体脂肪酸氧化密切相关，这是一种为TCA循环提供燃料的脂质催化剂途径。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性CD 8 T细胞的发育是必不可少的，Traf 6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检验这一假设：1）确定脂肪酸代谢如何调节记忆性CD 8 T细胞发育; 2）确定Traf 6依赖性调节记忆性CD 8 T细胞发育的程度; 3）确定CD 8 T细胞代谢的药理学操纵可以是治疗性的。这些研究的长期目标是促进针对感染性疾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.