Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, 62210 Cuernavaca, México.
Escuela de Estudios Superiores de Axochiapan, Universidad Autónoma del Estado de Morelos, 62951 Axochiapan, México.
Sci Signal. 2019 Apr 16;12(577):eaar3641. doi: 10.1126/scisignal.aar3641.
CD4 T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting model by analyzing how T cells responded to the activation of these pathways alone or in combination, in terms of the activation of the transcriptional regulators CREB, AP-1 (c-Jun), and NF-κB (p65). Our merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4 T cells.
CD4 T 细胞通过其 T 细胞受体（TCR）识别抗原；然而，适当的 T 细胞激活还需要涉及共刺激受体（例如 CD28）的其他信号。已经提出了替代的共刺激受体，包括 Toll 样受体（TLR）家族的成员，例如 TLR5 和 TLR2。为了理解 TLR5 潜在共刺激作用的分子机制，我们生成了 TCR 和 TLR5 信号通路的详细分子图谱和逻辑模型，以及这两个通路之间交叉相互作用的合并模型。此外，我们通过分析 T 细胞在单独或组合激活这些通路时，在转录调节剂 CREB、AP-1（c-Jun）和 NF-κB（p65）的激活方面的反应，验证了所得模型。我们的合并模型准确地预测了实验结果，表明 TLR5 的激活可以在 AP-1、CREB 和 NF-κB 激活方面发挥类似于 CD28 激活的作用，从而为 CD4 T 细胞中这些通路的交叉调节提供了见解。
