Mechanisms of ligand discrimination by the T cell signaling machinery

T 细胞信号传导机制的配体辨别机制

• 批准号: 10673732
• 负责人: Adam Courtney
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673732
• 关键词: Agonist; Cells; Chemicals; Complex; Coupled; Data Set; Discrimination; Disease; Ensure; Feedback; Genetic Transcription; Genomics; Goals; Human; Immunologics; Label; Ligand Binding; Ligands; Mass Spectrum Analysis; Michigan; Outcome; Phosphotransferases; Process; Property; Proteomics; Receptor Signaling; Regulation; Research; Resources; Scanning; Signal Transduction; Signaling Protein; Surface; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; Therapeutic; Universities; antigen-specific T cells; desensitization; extracellular; human disease; medical schools; novel strategies; prevent; protein complex; receptor; response; tool; transcriptome sequencing

SUMMARY T cells can discriminate between diseased and non-diseased states. To make this distinction, the information provided by extracellular receptors must be interpreted by signaling networks within the T cell. Most notable is T cell antigen receptor (TCR) signaling network because it combines a receptor that scans the surface of human cells for threats and signaling proteins that ensure a highly sensitive and specific response. This TCR signaling machinery can detect small quantities of an antigenic agonist and discriminate it from a background of structurally similar endogenous ligands. The overarching goal of my research group is to elucidate how the TCR signaling machinery discriminates between TCR ligands by producing distinct signaling outcomes. The past few decades have revealed how the TCR is coupled to signaling proteins within the T cell, but much less is known about how these signaling proteins are coordinated to produce different cellular responses, such as whether a TCR ligand should be ignored, or cause the T cell to become activated. The underlying mechanisms used to produce context- specific TCR signals must be determined to fully realize the potential of T cells as therapeutic entities for the treatment of human disease. Regulatory mechanisms can diversify signaling by controlling the activity of signaling proteins, such as kinases, and their assembly into protein complexes. We propose to determine how TCR signal diversification can arise from (1) negative feedback loops, (2) differential assembly of signaling complexes, and (3) adaptive desensitization of TCR signaling. To interrogate these mechanisms of signal diversification and their effect on a T cell response, we will combine chemical tools with immunological approaches. We will use proximity labeling and mass spectrometry analyses to determine how the composition of signaling complexes is altered by kinase-responsive negative feedback and TCR-ligand binding properties. We will also evaluate more long-term mechanisms of receptor desensitization caused by adaptive transcriptional changes by RNA sequencing. These datasets will be generated and analyzed with our collaborators at the University of Michigan Medical School, which includes the Proteomics Resource Facility and Advanced Genomics Core.

概括 T 细胞可以区分患病状态和非患病状态。为了做出这种区分，信息 细胞外受体提供的信号必须由 T 细胞内的信号网络进行解释。最值得注意的是T 细胞抗原受体（TCR）信号网络，因为它结合了扫描人体表面的受体 细胞的威胁和信号蛋白，确保高度敏感和特定的反应。这种TCR信号传导 机器可以检测少量的抗原激动剂并从结构背景中区分出来 类似的内源配体。我的研究小组的首要目标是阐明 TCR 信号传导如何 机器通过产生不同的信号结果来区分 TCR 配体。过去几十年 揭示了 TCR 如何与 T 细胞内的信号蛋白偶联，但对于如何偶联却知之甚少。 这些信号蛋白协调产生不同的细胞反应，例如 TCR 配体是否 应该被忽略，或者导致 T 细胞被激活。用于产生上下文的基本机制 必须确定特定的 TCR 信号，以充分发挥 T 细胞作为治疗实体的潜力 治疗人类疾病。调节机制可以通过控制信号的活动来使信号多样化 信号蛋白，例如激酶，及其组装成蛋白质复合物。我们建议确定如何 TCR 信号多样化可能来自 (1) 负反馈环路，(2) 信号的差分组装 (3) TCR 信号传导的适应性脱敏。询问这些信号机制 多样化及其对 T 细胞反应的影响，我们将化学工具与免疫学相结合 接近。我们将使用邻近标记和质谱分析来确定成分如何 信号复合物的结构受到激酶响应负反馈和 TCR 配体结合特性的改变。 我们还将评估适应性转录引起的受体脱敏的更长期机制。 通过 RNA 测序进行改变。这些数据集将与我们的合作者一起生成和分析 密歇根大学医学院，包括蛋白质组学资源设施和先进的 基因组学核心。