Control of memory and effector T cell differentiation & maintenance by the mitochondrial protein TCAIM

我们的初步数据显示，通过T细胞受体或常见γ链裸细胞因子受体（例如IL-2）接收的信号导致CD 4+和CD 8 + T细胞中tcaim表达的下调。TCAIM阻止T细胞受体刺激后的线粒体分裂和再分布，但也阻止朝向外周组织归巢效应和记忆T细胞的转录编程。因此，TCAIM各自的下调提供了T细胞受体信号、线粒体动力学和T细胞分化之间的联系。因此，我们假设，通过抑制线粒体分裂和再分配，TCAIM可以阻止代谢从初始T细胞中的主要氧化磷酸化转变为T细胞活化后的糖酵解。这对于组织归巢效应T细胞的分化和组织驻留记忆T细胞的维持至关重要。因此，我们将研究：1） 以及TCAIM如何控制线粒体融合或裂变调节蛋白的活化，从而控制T细胞中的细胞代谢，2） TCAIM防止细胞分裂期间线粒体的不对称分布，从而调节T细胞活化并抑制效应T细胞分化和组织归巢。 为了回答这些问题，我们将利用现有的组成型和诱导型（CD 4-CreERT 2/UBC-CreERT 2）T细胞特异性Tcaim tg/k.o.小鼠 前两个目标将通过应用分子生物学、代谢组学和成像技术的体外实验来实现。为了研究TCAIM是否干扰组织驻留记忆T细胞的维持，我们将利用流感感染模型并研究初次和二次流感攻击后病毒特异性CD 4 +/CD 8 + T细胞的数量、表型和功能。

Our preliminary data revealed that signals received via the T cell receptor or common gamma chain baring cytokine receptors (e.g. IL-2) result in a down-regulation of tcaim expression in CD4+ and CD8+ T cells. TCAIM prevents mitochondrial fission and redistribution upon T cell receptor stimulation but also transcriptional programming towards peripheral tissue homing effector and memory T cells. Thereby TCAIM respective its down-regulation provides a link between T cell receptor signals, mitochondrial dynamics and T cell differentiation. We thus hypothesize, that by inhibiting mitochondrial fission and redistribution TCAIM prevents the metabolic shift from mainly oxidative phosphorylation in naïve T cells towards glycolysis upon T cell activation. This is critical for the differentiation of tissue-homing effector T cells and maintenance of tissue-resident memory T cells. Thus we will study whether: 1) and how TCAIM controls activation of mitochondrial fusion or fission regulating proteins and thus cellular metabolism in T cells,2) TCAIM prevents asymmetric distribution of mitochondria during cell division thereby modulating T cell activation and inhibiting effector T cell differentiation and tissue homing.3) induction of tcaim expression interferes with the maintenance of tissue-resident memory T cells and whether this can be used to mobilize and re-differentiate effector and tissue-resident memory T cells into circulating less inflammatory memory T cells.To answer these questions, we will make use of existing constitutive and inducible (CD4-CreERT2/UBC-CreERT2) T cell-specific Tcaim tg/k.o. mice. The first two aims will be addressed with in vitro experiments applying molecular biology, metabolomics and imaging technologies. To investigate whether TCAIM interferes with the maintenance of tissue-resident memory T cells we will utilize the influenza infection model and study the number, phenotype and function of virus-specific CD4+/CD8+ T cells upon primary and secondary influenza challenge.