Understanding the Mechanisms of DC Licensing in CD8 T Cell Priming

了解 CD8 T 细胞启动中 DC 许可的机制

• 批准号: 10211694
• 负责人: Kenneth M Murphy
• 金额: $ 47.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211694
• 关键词: Antigen-Presenting Cells; Antigens; Antitumor Response; CD4 Positive T Lymphocytes; CD40 Ligand; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiolipins; Cell Communication; Cells; Cross Presentation; Data; Dendritic Cells; Development; Enhancers; Genes; Helper-Inducer T-Lymphocyte; Individual; Knowledge; Licensing; Ligands; Lipids; Methods; Modeling; Mus; Nature; Pathway interactions; Process; Publishing; Role; Side; Signal Transduction; Source; T cell response; T-Cell Receptor; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Time; Transgenic Organisms; Tumor Immunity; Tumor-Derived; Virus; Work; arm; base; cell type; in vivo; neoantigens; new therapeutic target; novel; pathogen; programs; response; transcription factor; tumor; γδ T cells

ABSTRACT Effective responses to viruses, intracellular pathogens and tumors rely on the successful expansion and arming of cytolytic CD8 T cells from a naïve and quiescent T cell repertoire. This process, called CD8 T cell priming, is dependent on a specialized antigen-presenting cell known as conventional dendritic cells (cDCs). Recent studies from our lab have shown that a specific type of dendritic cells, called cDC1, is responsible for CD8 T cell priming and depends on the transcription factor Batf3 for development. In the process of priming CD8 T cells, the cDC1 captures foreign antigens or tumor-specific neo-antigens, and presents these antigens on the MHC-I molecule in order to stimulate the T cell receptor (TCR) of the CD8 T cell. In the absence of cDC1, such as in Batf3-deficient mice, CD8 T cells are not activated against viruses or tumors. In addition, however, full activation of CD8 T cell requires that cDC1 receive signals that program its ability to fully activate CD8 T cells. This process is called `DC licensing', but is currently not fully characterized. Our recent work has shown that current models for DC licensing are incomplete. Specifically, while we have confirmed the requirement for CD40 signaling in response to CD40L provided by a helper cell, we have shown that the expected target of CD40, CD70, does not explain the beneficial effect of DC licensing for tumor rejection. This result implies that additional targets of CD40 are needed to understand DC licensing. Further, it has been thought that CD4 T cells are the exclusive agent in the licensing process. However, these conclusions derived from older studies and less precise methods. In contrast, we developed an Xcr1-Cre deletor strain to delete genes specifically from cDC1, and found unexpected results, that CD4 T cells are not always critical for cDC1 licensing, suggesting that other cells expressing CD40L may be involved. Further, mechanism by which CD40 signaling induces licensing of the cDC1 is unclear. Several mechanisms have been proposed, but our preliminary data excludes the major proposed mechanism, those invoking CD70, as being critical for the effect of licensed cDC1 in priming CD8 T cells. Our proposal will first test (Aim 1) which Batf3-specific genes expressed in cDC1 are important for cDC1 to support CD8 T cells responses. Second (Aim 2), we will determine identify the targets of CD40 signaling in cDC1 that are required for fully activating CD8 T cells. Finally, in Aim 3, we will test the role of cells that we have identified as alternative sources of CD40 ligand, including iNKT cells and γδ T cells.

抽象的 对病毒、细胞内病原体和肿瘤的有效反应依赖于来自幼稚和静止 T 细胞库的溶细胞 CD8 T 细胞的成功扩增和武装。这个过程称为 CD8 T 细胞启动，依赖于一种称为传统树突细胞 (cDC) 的特殊抗原呈递细胞。我们实验室最近的研究表明，一种称为 cDC1 的特定类型的树突状细胞负责 CD8 T 细胞启动并依赖转录因子 Batf3 进行发育。在启动 CD8 T 的过程中 细胞中，cDC1捕获外来抗原或肿瘤特异性新抗原，并将这些抗原呈递到细胞上。 MHC-I 分子以刺激 CD8 T 细胞的 T 细胞受体 (TCR)。在没有 cDC1 的情况下，这样 与 Batf3 缺陷小鼠一样，CD8 T 细胞不会被激活来对抗病毒或肿瘤。然而除此之外，满 CD8 T 细胞的激活需要 cDC1 接收信号来编程其完全激活 CD8 T 细胞的能力。 该过程称为“DC 许可”，但目前尚未完全表征。我们最近的工作表明 当前的 DC 许可模型并不完整。具体来说，虽然我们已经确认了以下要求 CD40 信号响应辅助细胞提供的 CD40L，我们已经表明预期的目标 CD40、CD70并不能解释DC许可对肿瘤排斥的有益作用。这个结果意味着 需要 CD40 的其他目标来理解 DC 许可。此外，人们认为 CD4 T cells是许可过程中的独家代理。然而，这些结论来自较早的研究 以及不太精确的方法。相比之下，我们开发了 Xcr1-Cre 删除菌株来特异性删除基因 并发现了意想不到的结果，即 CD4 T 细胞对于 cDC1 许可并不总是至关重要，这表明表达 CD40L 的其他细胞可能也参与其中。此外，CD40信号传导诱导的机制 CDC1 的许可情况尚不清楚。已经提出了几种机制，但我们的初步数据不包括 主要提出的机制，即调用 CD70 的机制，对于许可的 cDC1 在启动 CD8 T 细胞中的作用至关重要。我们的建议将首先测试（目标 1）cDC1 中表达的哪些 Batf3 特异性基因是重要的 cDC1 支持 CD8 T 细胞反应。第二（目标2），我们将确定CD40的靶标 充分激活 CD8 T 细胞所需的 cDC1 信号传导。最后，在目标3中，我们将测试细胞的作用 我们已确定 CD40 配体的替代来源，包括 iNKT 细胞和 γδ T 细胞。