PDF(Pubmed)
Abstract：
The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats.
摘要：
免疫系统在其形成的记忆细胞的数量和类型中编码有关致病威胁的严重性的信息。这种编码来自淋巴细胞决定在攻击期间维持或失去自我更新和记忆潜力。通过使用时间分辨转录组学在单细胞和克隆谱系水平跟踪CD8+T细胞，定量实时成像，和急性感染模型，我们发现T细胞会在抗原识别后早期维持或丧失记忆潜能。然而,病原体清除后，如果最初丢失，T细胞可能会恢复记忆潜能。机械上,这种灵活性是通过一个随机的顺式-表观遗传开关来实现的，该开关可调谐和可逆地使记忆调节器沉默，TCF1，对刺激的反应。数学建模显示了这种灵活性如何使记忆T细胞数量随着病原体毒力和免疫应答幅度而稳健地扩展。我们建议细胞决策的灵活性和随机性确保针对各种威胁的最佳免疫反应。
