How the T cell signaling network processes information to discriminate between self and agonist ligands
How the T cell signaling network processes information to discriminate between self and agonist ligands
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DOI：
10.1073/pnas.2008303117
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发表时间：
2020-10-20
影响因子：
11.1
通讯作者：
Chakraborty, Arup K.
中科院分区：
文献类型：
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作者：
Ganti, Raman S.;Lo, Wan-Lin;Chakraborty, Arup K.
T细胞在检测和响应与自身pMHC分子海洋中的MHC分子结合的激动剂肽（p）方面表现出显著的敏感性和选择性。尽管做了很多工作，但对区分这些配体的潜在机制的理解仍然不完整。在这里，我们量化T细胞的歧视能力，使用通道的能力，直接测量的信号网络的能力，区分抗原呈递细胞（APC）显示自身配体或自身和激动剂配体的混合物。这个指标显示了这两种类型的肽段之间的信息内容差异是如何通过T细胞内的拓扑结构和动力学校正信号步骤的速率来解码的。使用通道容量，我们构建了数字证实的假设来解释最近发现的一个缓慢的LAT Y132磷酸化步骤的歧视作用。我们的研究结果表明，除了顺序信号步骤的数量和动力学，判别能力的一个关键决定因素是空间定位的最小数量的这些步骤的参与TCR。生物化学和成像实验支持这些发现。我们的研究结果还揭示了早期负反馈和后期正反馈所赋予的必要放大的歧视作用。
T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing such ligands remains incomplete. Here, we quantify T cell discriminatory capacity using channel capacity, a direct measure of the signaling network's ability to discriminate between antigen-presenting cells (APCs) displaying either self ligands or a mixture of self and agonist ligands. This metric shows how differences in information content between these two types of peptidomes are decoded by the topology and rates of kinetic proofreading signaling steps inside T cells. Using channel capacity, we constructed numerically substantiated hypotheses to explain the discriminatory role of a recently identified slow LAT Y132 phosphorylation step. Our results revealed that in addition to the number and kinetics of sequential signaling steps, a key determinant of discriminatory capability is spatial localization of a minimum number of these steps to the engaged TCR. Biochemical and imaging experiments support these findings. Our results also reveal the discriminatory role of early negative feedback and necessary amplification conferred by late positive feedback.