Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity

CD 8 + T淋巴细胞是建立保护性细胞免疫应答的重要参与者， 病原体和恶性转化的细胞。取决于抗原攻击的性质，CD 8 + T细胞是免疫性的。 具有一定水平的可塑性，以最大限度地减少感染或肿瘤细胞。病原体后 由于急性感染导致的清除，记忆CD 8 + T细胞长期存在，并提供增强的免疫应答。 对相同或相关病原体的保护，这些特征构成了预防的基础。 疫苗。另一方面，作为慢性感染和癌症的结果，抗原持续存在导致CD 8 + T细胞减少。 细胞衰竭或功能障碍;尽管如此，耗尽的CD 8 + T（Tex）细胞可以部分恢复活力， 最近在癌症免疫治疗中成功的检查点阻断。 了解T细胞记忆和耗竭的分子电路对于充分利用T细胞的功能至关重要。 细胞毒性CD 8 + T细胞提高病毒或癌症免疫力的潜力。在这次竞争激烈的续约中 我们的目标是揭示Tcf 1及其HDAC活性与染色质可及性的未知联系 以及记忆和耗竭的CD 8 + T细胞中基于染色质环的增强子-启动子相互作用。的 具体目标如下： 目标1.研究Tcf 1预编程如何增强记忆CD 8 + T细胞的回忆反应。 记忆性CD 8 + T细胞通过更稳健的增殖和更快速的激活表现出增强的回忆应答 的细胞溶解活性。一个主要的知识差距仍然是关于分子基础， 增强免疫反应的分子调节器。我们假设Tcf 1前编程 中央记忆CD 8 + T细胞对回忆刺激的反应性增强。我们将使用无偏 系统生物学方法，包括DNase-seq和HiC，以确定Tcf 1及其HDAC活性如何控制 染色质可及性和成环。结合全面的功能学研究，我们将进行深入的 解剖独特的分子线路，决定了Tcm细胞增强的回忆反应。 目标2.确定Tcf 1促进衰竭的CD 8 + T细胞功能恢复的能力。 最近的进展显示，慢性感染引起的Tex细胞含有CXCR 5 + Tim 3亚群， 干细胞样自我更新能力，并表达升高水平的Tcf 1。我们假设Tcf 1- 依赖性调节回路可用于持久地增强Tex功能恢复。我们将测试各种 慢性病毒感染和肿瘤模型中的Tcf 1形式和辅因子组合，并确定其影响 染色质可及性/循环及其与Tex细胞有利功能输出的联系。 该提案将机械地阐明Tcf 1如何编排3D基因组以编程记忆CD 8+， 耗尽的CD 8 + T细胞，以增强功能输出，并提供及时的，急需的见解，设计 更有效的疫苗和治疗传染病和癌症的药物。

CD8+ T lymphocytes are essential players in mounting protective cellular immune responses against pathogens and malignantly transformed cells. Depending on the nature of antigen challenge, CD8+ T cells are equipped with certain levels of plasticity to maximize reduction of infected or tumor cells. After pathogen clearance resulting from acute infections, memory CD8+ T cells persist for long term and provide enhanced protection against the same or related pathogens, and these features constitute the basis for prophylactic vaccines. On the other hand, antigen persistence, as a result of chronic infection and cancers, causes CD8+ T cell exhaustion or dysfunction; nonetheless, the exhausted CD8+ T (Tex) cells can be partly reinvigorated, as seen in recent success of checkpoint blockade in cancer immunotherapy. Understanding molecular circuits that underlie T cell memory and exhaustion is critical for fully harnessing the potentials of cytotoxic CD8+ T cells for improving viral or cancer immunity. In this competitive renewal application, our goal is to uncover the uncharted links of Tcf1 and its HDAC activity with chromatin accessibility and chromatin looping-based enhancer-promoter interactions in memory and exhausted CD8+ T cells. The specific aims are as follows: Aim 1. To investigate how Tcf1 preprograms enhanced recall responses by memory CD8+ T cells. Memory CD8+ T cells exhibit enhanced recall response by more robust proliferation and more rapid activation of cytolytic activities than naïve T cells. A major knowledge gap remains regarding the molecular basis and molecular regulators that underlie the heightened immune response. We hypothesize that Tcf1 preprograms central memory CD8+ T cells for their enhanced responsiveness to recall stimulation. We will use unbiased systems biology approaches including DNase-seq and HiC to define how Tcf1 and its HDAC activity control chromatin accessibility and looping. Combined with comprehensive functional studies, we will perform in-depth dissection of the unique molecular wiring that dictates enhanced recall responses by Tcm cells. Aim 2. To determine the capacity of Tcf1 to enhance functional restoration of exhausted CD8+ T cells. Recent advances revealed that Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1. We hypothesize that Tcf1- dependent regulatory circuits can be utilized to durably enhance Tex functional restoration. We will test various Tcf1 forms and cofactor combinations in chronic viral infection and tumor models, and determine their impact on chromatin accessibility/looping and its link to favorable functional output by Tex cells. This proposal will mechanistically elucidate how Tcf1 orchestrates 3D-genome to program memory CD8+ and exhausted CD8+ T cells for enhanced functional output, and provide timely, much needed insights into devising more effective vaccines and therapeutics for infectious diseases and cancers.