TLR4 signaling in stromal cells is critical for the initiation of allergic Th2 responses to inhaled antigen

Allergic asthma is an inflammatory lung disease driven by Th2.We have shown that both Th1 and Th2 sensitization to inhaled OVA depend on the presence and concentration of LPS, where high concentrations (LPS^hi) induce Th1 and low concentrations (LPS^lo), Th2. Stromal cells (SCs), such as airway SCs, exacerbate established airway disease; however, little is known about their role early during sensitization. In this study, using bone marrow chimeric mice to restrict TLR4 signaling to either the SC compartment (SC ⁺HPC^-) or the hematopoietic cell (HPC) compartment (SC^-HPC⁺), we report that HPC TLR4 is necessary and sufficient for Th1 sensitization to OVA-LPS^hi, whereas TLR4 in both compartments is required for Th2 sensitization to OVA-LPS^lo. Surprisingly, although SC⁺HPC^- mice were unable to generate a Th1 response to OVA-LPS^hi, they instead mounted a robust Th2 response, indicating that in the presence of higher concentrations of LPS, SC TLR4 is sufficient for Th2 sensitization. We show that the SC TLR4 response to LPS leads to induction of Th2-inducing dendritic cells that upregulate Notch ligand Jagged-1 but not Delta-4. Furthermore, airway SCs upregulate thymic stromal lymphopoietin in response to exposure to both OVA-LPS^lo and OVA-LPS^hi. These studies demonstrate that SC TLR4 signaling is critically involved in Th2 but not Th1 sensitization to inhaled Ag.