Voisinne Guillaume, Nixon Briana G, Melbinger Anna, Gasteiger Georg, Vergassola Massimo, Altan-Bonnet Grégoire
Cell Rep. 2015 May 26;11(8):1208-19. doi: 10.1016/j.celrep.2015.04.051.
T lymphocytes’ ability to discriminate between structurally related antigens has been attributed to the unique signaling properties of the T cell receptor. However, recent studies have suggested that the output of this discrimination process is conditioned by environmental cues. Here, we demonstrate how the IL-2 cytokine, collectively generated by strongly activated T cell clones, can induce weaker T cell clones to proliferate. We identify the PI3K pathway as being critical for integrating the antigen and cytokine responses and for controlling cell-cycle entry. We build a hybrid stochastic/deterministic computational model that accounts for such signal synergism and demonstrates quantitatively how T cells tune their cell-cycle entry according to environmental cytokine cues. Our findings indicate that antigen discrimination by T cells is not solely an intrinsic cellular property but rather a product of integration of multiple cues, including local cues such as antigen quality and quantity, to global ones like the extracellular concentration of inflammatory cytokines.
T淋巴细胞区分结构相关抗原的能力一直归因于T细胞受体独特的信号特性。然而，最近的研究表明，这种区分过程的结果受到环境线索的制约。在这里，我们展示了由强烈激活的T细胞克隆共同产生的白细胞介素-2细胞因子如何诱导较弱的T细胞克隆增殖。我们确定PI3K信号通路对于整合抗原和细胞因子反应以及控制细胞周期进入至关重要。我们构建了一个混合随机/确定性计算模型，该模型解释了这种信号协同作用，并定量地展示了T细胞如何根据环境细胞因子线索调节其细胞周期进入。我们的研究结果表明，T细胞对抗原的区分不仅仅是一种内在的细胞特性，而是多种线索整合的产物，包括局部线索如抗原质量和数量，以及全局线索如炎症细胞因子的细胞外浓度。
