University of Washington, Department of Bioengineering, Seattle, WA 98195.
University of Washington, Department of Genome Sciences, Seattle, WA 98195.
Proc Natl Acad Sci U S A. 2023 Dec 26;120(52):e2308366120. doi: 10.1073/pnas.2308366120. Epub 2023 Dec 19.
Immune system threat detection hinges on T cells' ability to perceive varying peptide-major histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs but diverge only over longer (9+ h) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception and establish a framework for understanding T cell responses under diverse contexts.
免疫系统威胁检测取决于 T 细胞感知不同肽-主要组织相容性复合体 (pMHC) 抗原的能力。由于 Erk 和 NFAT 途径将 T 细胞受体结合与基因调控联系起来，它们的信号转导动力学可能传递关于 pMHC 输入的信息。为了验证这一想法，我们开发了一种双报告小鼠品系和一种定量成像测定法，这两种方法结合在一起，能够在活 T 细胞对不同 pMHC 输入作出反应时，在长达一天的时间尺度上同时监测 Erk 和 NFAT 动力学。两条途径最初在各种 pMHC 输入下均匀激活，但仅在较长时间（9+ 小时）尺度上才会发散，从而能够独立编码 pMHC 亲和力和剂量。这些晚期信号转导动力学通过多种时间和组合机制进行解码，以产生 pMHC 特异性转录反应。我们的研究结果强调了在抗原感知中长时标信号转导动力学的重要性，并为在不同背景下理解 T 细胞反应建立了一个框架。
