Cooperation between T cell receptor and Toll-like receptor 5 signaling for CD4 + T cell activation
CD4 + T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving co-stimulatory receptors, for example CD28, are required for proper T cell activation. Alternative co-stimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying this co-stimulatory function, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways, together with a merged model accounting for cross-interactions. Furthermore, we validated the resulting model by analyzing the responses of T cells 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-B (p65). Our merged model accurately reproduces 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-кB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4 + T cells.