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; 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从幼稚和静止的T细胞库中的细胞溶解CD8 T细胞的成功膨胀和武装。该过程称为CD8 T细胞启动，取决于称为常规树突状细胞（CDC）的专门抗原细胞。我们实验室的最新研究表明，一种称为CDC1的特定类型的树突状细胞负责CD8 T细胞启动并取决于转录因子BATF3进行开发。在启动CD8 T的过程中 细胞，CDC1捕获异物抗原或肿瘤特异性新抗原，并将这些抗原呈现在 MHC-I分子是为了刺激CD8 T细胞的T细胞受体（TCR）。在没有CDC1的情况下 与BATF3缺乏小鼠一样，CD8 T细胞未针对病毒或肿瘤激活。但是，还满 CD8 T细胞的激活要求CDC1接收信号，以使其完全激活CD8 T细胞的能力。 此过程称为“ 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许可模型不完整。具体而言，尽管我们已经确认了要求 CD40信号传导响应辅助电池提供的CD40L，我们表明 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 需要其他CD40的目标来了解直流许可。此外，人们认为CD4 T 细胞是许可过程中的独家代理。但是，这些结论来自较旧的研究 和不太精确的方法。相比之下，我们开发了一个XCR1-CRE DELERER菌株以删除基​​因 从CDC1并发现了意外的结果，CD4 T细胞对于CDC1许可并不总是至关重要的，这表明可能涉及其他表达CD40L的细胞。此外，CD40信号引起的机制 CDC1的许可尚不清楚。已经提出了几种机制，但是我们的初步数据不包括 拟议的主要机制是调用CD70的机制，对于启动CD8 T细胞中许可CDC1的影响至关重要。我们的建议将首先测试哪个在Cdc1中表达的BATF3特异性基因很重要 CDC1支持CD8 T细胞响应。第二（AIM 2），我们将确定确定CD40的目标 完全激活CD8 T细胞所需的CDC1信号。最后，在AIM 3中，我们将测试细胞的作用 我们已经确定为CD40配体的替代来源，包括inkt细胞和γδT细胞。