Molecular Mechanisms of TOX-mediated Programming of CD8 T Cell Exhaustion

TOX 介导的 CD8 T 细胞耗竭编程的分子机制

基本信息

  • 批准号:
    10606385
  • 负责人:
  • 金额:
    $ 5.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY CD8 T cell responses to viral infections and tumors contribute significantly to the immune responses that dictate the clinical outcomes of such pathologies. The functional integrity of CD8 T cell responses depends on the characteristic properties of CD8 effector (Teff) and memory (Tmem) populations. However, during chronic viral infections and cancer, antigen persistence without clearance precludes effective Teff and Tmem development, instead biasing CD8 T cell differentiation towards an epigenetically distinct “exhausted” lineage (Tex). Tex exhibit progressive dysfunction and loss of effector properties, proliferation capacity, and memory potential, as well as a sustained increase in co-expression of PD1 and multiple other inhibitory receptors (IRs). Interrogating the fundamental mechanisms that initiate and maintain the Tex epigenetic state is of central importance to understanding Tex biology and identifying strategies to selectively target or modulate Tex. However, the field generally lacks a detailed mechanistic understanding of Tex-specific epigenetic processes. In models of exhaustion during chronic infection and of dysfunctional tumor-specific T cells, the transcription factor TOX is essential for the initiation of Tex development, repressing terminal Teff differentiation and potentiating epigenetic commitment to the Tex lineage. This proposal seeks to identify and interrogate the mechanistic details of Tex regulation by TOX that would be required to begin developing immunotherapy approaches to epigenetically reprogram Tex and improve immunotherapy clinical outcomes. The molecular transactions TOX employs to exert its effects remain largely unknown. Understanding the details of TOX activity remains limited by a lack of functional characterization of its N- and C-terminal domains (“NTD” and “CTD”) in relation to its HMG-box DNA binding domain. My preliminary data demonstrate in vitro that loss of either the TOX NTD or CTD is sufficient to abrogate the increase in surface PD1 expression that is characteristically driven by full-length (“FL”) TOX, suggesting important, as yet unknown roles for these domains. The central hypothesis of this proposal is that distinct features of TOX activity are attributable to its N- vs. C-terminal domains and that NTD- or CTD-specific perturbations will enable selective modulation of Tex responses to chronic viral infection. This proposal tests this hypothesis by interrogating features of TOX’s interactions and domain-level function at the Pdcd1 locus (encoding PD1), by defining the extent to which the NTD and CTD exhibit global differences in their Tex-specific roles, by defining how the NTD and CTD program the Tex epigenetic state, and by determining which NTD- and CTD-mediated protein interactions TOX uses to regulate Tex transcription. This proposal will thus advance fundamental knowledge of how the molecular processes regulating exhaustion may be manipulated to improve CD8 T cell responses during chronic viral infections and cancer.
项目总结 CD8T细胞对病毒感染和肿瘤的反应对免疫反应有重要贡献 决定了这种病理的临床结果。CD8 T细胞反应的功能完整性取决于 CD8效应器(Tef)和记忆(TMEM)群体的特征。然而,在慢性 病毒感染和癌症,没有清除的抗原持久性排除了有效的TEFF和TMEM 发育,而不是偏向CD8 T细胞分化为表观遗传学上独特的“疲惫”谱系 (特克斯)。TeX表现为进行性功能障碍和效应器特性、增殖能力和记忆力的丧失 潜在的,以及PD1和多个其他抑制性受体(IR)共表达的持续增加。 询问启动和维持TeX表观遗传状态的基本机制是至关重要的 了解Tex生物学和确定选择性靶向或调节Tex的策略的重要性。 然而,该领域普遍缺乏对TeX特定表观遗传过程的详细机制理解。在……里面 慢性感染时的衰竭模型和功能失调的肿瘤特异性T细胞,转录因子 毒素对Tex发育的启动、抑制末端Tef的分化和增强是必不可少的 对德州血统的表观遗传承诺。这项提议寻求确定和审问机械性细节 TOX对Tex的调节,这将是开始开发免疫治疗方法所必需的 对TeX进行表观遗传学重新编程,改善免疫治疗的临床结果。 TOX用来发挥其作用的分子交易在很大程度上仍不清楚。了解细节 TOX活性的研究仍然受到其N-末端和C-末端结构域(“NTD”)功能特性的限制 和“CTD”)与其HMG-box DNA结合域相关。我的初步数据显示,在体外, TOX NTD或CTD足以消除表面PD1表达的增加,即 特征是由全长(“FL”)TOX驱动,暗示这些结构域具有重要的、尚不清楚的作用。 这一建议的中心假设是,TOX活性的明显特征可归因于其N- 以及NTD或CTD特定扰动将使得能够选择性地调制 对慢性病毒感染的TeX反应。这项建议通过询问TOX的特征来检验这一假设 Pdcd1基因座(编码PD1)的相互作用和域级功能,通过定义 NTD和CTD通过定义NTD和CTD计划如何在其特定于TeX的角色中展示全球差异 TeX表观遗传状态,并通过确定TOX使用哪种NTD和CTD介导的蛋白质相互作用来实现 调节TeX转录。因此,这一提议将推进对分子如何 调节耗竭的过程可能被操纵以改善慢性病毒期间的CD8 T细胞反应 感染和癌症。

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