Wither Matthew J, White William L, Pendyala Sriram, Leanza Paul J, Fowler Doug, Kueh Hao Yuan
bioRxiv. 2023 Jun 5:2023.06.01.543260. doi: 10.1101/2023.06.01.543260.
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+ hrs) 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.
To counter diverse pathogens, T cells mount distinct responses to varying peptide-major histocompatibility complex ligands (pMHCs). They perceive the affinity of pMHCs for the T cell receptor (TCR), which reflects its foreignness, as well as pMHC abundance. By tracking signaling responses in single living cells to different pMHCs, we find that T cells can independently perceive pMHC affinity vs dose, and encode this information through the dynamics of Erk and NFAT signaling pathways downstream of the TCR. These dynamics are jointly decoded by gene regulatory mechanisms to produce pMHC-specific activation responses. Our work reveals how T cells can elicit tailored functional responses to diverse threats and how dysregulation of these responses may lead to immune pathologies.
免疫系统的威胁检测取决于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信号通路将T细胞受体的激活与基因调控联系起来，它们的信号转导动力学可能传达有关pMHC输入的信息。为了验证这一想法，我们开发了一种双报告基因小鼠品系和一种定量成像检测方法，二者结合能够在长达一天的时间尺度上同时监测活T细胞在对不同pMHC输入作出反应时的Erk和NFAT动力学。这两条信号通路在各种pMHC输入下最初均会均匀激活，但仅在较长（9小时以上）的时间尺度上出现分化，从而能够对pMHC亲和力和剂量进行独立编码。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长时间尺度信号转导动力学在抗原识别中的重要性，并建立了一个理解不同背景下T细胞反应的框架。
为了对抗多种病原体，T细胞对不同的肽-主要组织相容性复合体配体（pMHC）产生不同的反应。它们能够感知pMHC对T细胞受体（TCR）的亲和力，这反映了其异己性，以及pMHC的丰度。通过追踪单个活细胞对不同pMHC的信号反应，我们发现T细胞能够独立感知pMHC的亲和力与剂量，并通过TCR下游的Erk和NFAT信号通路的动力学对这些信息进行编码。这些动力学通过基因调控机制共同解码，以产生pMHC特异性激活反应。我们的工作揭示了T细胞如何对各种威胁引发量身定制的功能反应，以及这些反应的失调如何可能导致免疫病理。
