Role of hematopoietic and stromal cell Toll-like receptor 4 signaling in the initiation of Th1 and Th2 adaptive immune responses

Allergic asthma is an inflammatory lung disease driven by T helper cells type 2 (Th2). Airway epithelial cells are known to play a role in the exacerbation of previously established airway disease; however, their role in the early events that govern the establishment of allergic disease is not known. Here, using studies in chimeric and transgenic mice, we report for the first time that the airway epithelial cell is the critical Toll-like receptor 4 (TLR4) signaling cell that drives the development of Th2-mediated allergic airway disease to inhaled antigen containing LPS. Bone marrow chimeric mice lacking TLR4 in the stromal compartment of the lung fail to mount Th2 responses to inhaled ovalbumin. Furthermore, bone marrow chimeric mice only expressing TLR4 in the stromal cells of the lung and transgenic mice only expressing TLR4 in airway epithelial cells (AECs) sensitized with OVA and high levels of lipopolysaccharide (LPS) mount exaggerated Th2 responses following airway challenge with antigen. AECs upregulate thymic stromal lymphopoietin mRNA and protein expression and induce dendritic cells to undergo a program of maturation favoring the polarization of Th2 but not Th1 effector cells following exposure to LPS. These studies show that the AEC response to LPS, a microbial TLR ligand associated with common aeroallergens, is the critical factor driving the development of Th2 adaptive immune responses to aeroallergens.