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.

摘要 对病毒、细胞内病原体和肿瘤的有效应答依赖于从幼稚和静止T细胞库成功扩增和武装溶细胞性CD 8 T细胞。这一过程称为CD 8 T细胞引发，依赖于一种称为常规树突状细胞（cDC）的特化抗原呈递细胞。我们实验室最近的研究表明，一种特殊类型的树突状细胞，称为cDC 1，负责CD 8 T细胞启动并依赖于转录因子Batf 3进行发育。在启动CD 8 T细胞的过程中， 在细胞中，cDC 1捕获外源抗原或肿瘤特异性新抗原，并将这些抗原呈递到细胞上。 在一些实施方案中，CD 8 T细胞可以与MHC-I分子结合以刺激CD 8 T细胞的T细胞受体（TCR）。在不存在cDC 1的情况下，这样的 在Batf 3缺陷小鼠中，CD 8 T细胞不被激活以对抗病毒或肿瘤。此外，全面 CD 8 T细胞的活化需要cDC 1接收信号，该信号对其完全活化CD 8 T细胞的能力进行编程。 这一过程被称为“发展中国家许可证发放”，但目前尚未完全确定。我们最近的工作表明， 目前的DC许可模式是不完整的。具体而言，虽然我们已经确认了 CD 40信号对辅助细胞提供的CD 40 L的应答，我们已经表明， CD 40、CD 70不能解释DC许可对肿瘤排斥的有益作用。这一结果意味着， 需要额外的CD 40靶点来理解DC许可。此外，已经认为CD 4 T 细胞是许可过程中的唯一代理。然而，这些结论来自更早的研究， 不太精确的方法。相比之下，我们开发了一种Xcr 1-Cre缺失菌株， 从cDC 1，并发现了意想不到的结果，CD 4 T细胞并不总是cDC 1许可的关键，这表明其他细胞表达CD 40 L可能参与。此外，CD 40信号传导诱导 cDC 1的许可尚不清楚。已经提出了几种机制，但我们的初步数据排除了 主要提出的机制，那些调用CD 70，作为关键的许可的cDC 1在启动CD 8 T细胞的效果。我们的建议将首先测试（目标1）在cDC 1中表达的哪些Batf 3特异性基因是重要的 cDC 1支持CD 8 T细胞应答。第二（目标2），我们将确定识别CD 40的靶点 cDC 1中的信号传导是完全激活CD 8 T细胞所需的。最后，在目标3中，我们将测试细胞的作用 我们已经鉴定为CD 40配体的替代来源，包括iNKT细胞和γδ T细胞。