<scp>TNF</scp>‐alpha is a key mediator in the development of <scp>T</scp>h2 cell response to inhaled allergens induced by a viral <scp>PAMP</scp> double‐stranded <scp>RNA</scp>

Abstract

BACKGROUND: Viral pathogen-associated molecular patterns, such as dsRNA, disrupt airway tolerance to inhaled allergens. Specifically, the Th2 and Th17 cell responses are induced by low-dose dsRNA and the Th1-dominant response by high-dose dsRNA. OBJECTIVE: In this model, we evaluate the role of TNF-α in the development of adaptive immune dysfunction to inhaled allergens induced by airway sensitization with dsRNA-containing allergens. METHODS: A virus-associated asthma mouse model was generated via simultaneous airway administration of ovalbumin (OVA) and low (0.1 μg) or high (10 μg) doses of polyinosine-polycytidylic acid (poly[I:C]). The effect of TNF-α on Th2 airway inflammation was evaluated using TNF-α-deficient mice and recombinant TNF-α. RESULTS: TNF-α production was enhanced by airway exposure to low and high doses of poly[I:C]. After airway sensitization with OVA plus low-dose poly[I:C], TNF-α-deficient mice exhibited less OVA-induced airway inflammation than did wild-type (WT) mice. However, this did not occur upon sensitization with high-dose poly[I:C]. In terms of T-cell response, the production of IL-4 from lung T cells after OVA challenge was enhanced by airway sensitization with OVA plus low-dose poly[I:C] in WT mice, and this phenotype was inhibited by the absence of TNF-α. Moreover, the Th2 cell response induced by sensitization with OVA plus low-dose poly[I:C], which was abolished in TNF-α-deficient mice, was restored in these mice upon addition of recombinant TNF-α. CONCLUSION: The results of this study suggest that TNF-α produced by airway exposure to low-dose dsRNA is a key mediator in the development of Th2 cell response to inhaled allergens.