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反应依赖于从幼稚和静止的T细胞库中成功地扩增和武装具有细胞毒性的CD8T细胞。这一过程被称为CD8T细胞启动，依赖于一种特殊的抗原提呈细胞，称为常规树突状细胞(CDCs)。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cDc1，负责CD8 T细胞的启动和依赖转录因子BATF3的发育。在启动CD8 T细胞的过程中 细胞，cDC1捕获外来抗原或肿瘤特异性新抗原，并将这些抗原呈现在 MHC-I分子，以刺激CD8T细胞的T细胞受体(TCR)。在没有cdc1的情况下， 与BATF3基因缺陷的小鼠一样，CD8T细胞不会被病毒或肿瘤激活。然而，除此之外，完整的 CD8T细胞的激活需要cDC1接收信号来编程其完全激活CD8T细胞的能力。 这一过程被称为“DC许可”，但目前还没有完全确定其特征。我们最近的研究表明， 目前的DC许可模式是不完整的。具体地说，虽然我们已经确认了 CD40信号响应辅助细胞提供的CD40L，我们已经证明了预期的靶点 CD40、CD70不能解释DC许可对肿瘤排斥的有益效果。这一结果意味着 要理解DC许可，还需要CD40的其他目标。此外，人们还认为CD4T CELL是许可过程中的独家代理。然而，这些结论来自于较早的研究 以及不太精确的方法。相反，我们开发了一种Xcr1-Cre缺失菌株来特异性地删除基因 结果发现，CD4T细胞并不总是对cDC1的许可至关重要，这表明表达CD40L的其他细胞可能参与了这一过程。此外，CD40信号诱导的机制 CDC1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 主要建议的机制，即那些调用CD70的机制，对于授权的CDC1在启动CD8T细胞方面的效果至关重要。我们的建议将首先测试(目标1)哪些BATF3特异性基因在cDC1中表达是重要的 以支持CD8 T细胞反应。第二个(目标2)，我们将确定CD40的靶点 CD8T细胞完全激活所需的CDC1中的信号。最后，在目标3中，我们将测试细胞的作用 我们已经确定CD40L的替代来源，包括iNKT细胞和γδT细胞。