IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction

M Kudo, AC Melton, C Chen, MB Engler, KE Huang… - Nature medicine, 2012 - nature.com
M Kudo, AC Melton, C Chen, MB Engler, KE Huang, X Ren, Y Wang, X Bernstein, JT Li…
Nature medicine, 2012nature.com
Emerging evidence suggests that the T helper 17 (TH17) subset of αβ T cells contributes to
the development of allergic asthma. In this study, we found that mice lacking the αvβ8
integrin on dendritic cells did not generate TH17 cells in the lung and were protected from
airway hyper-responsiveness in response to house dust mite and ovalbumin sensitization
and challenge. Because loss of TH17 cells inhibited airway narrowing without any obvious
effects on airway inflammation or epithelial morphology, we examined the direct effects of …
Abstract
Emerging evidence suggests that the T helper 17 (TH17) subset of αβ T cells contributes to the development of allergic asthma. In this study, we found that mice lacking the αvβ8 integrin on dendritic cells did not generate TH17 cells in the lung and were protected from airway hyper-responsiveness in response to house dust mite and ovalbumin sensitization and challenge. Because loss of TH17 cells inhibited airway narrowing without any obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of TH17 cytokines on mouse and human airway smooth muscle function. Interleukin-17A (IL-17A), but not IL-17F or IL-22, enhanced contractile force generation of airway smooth muscle through an IL-17 receptor A (IL-17RA)–IL-17RC, nuclear factor κ light-chain enhancer of activated B cells (NF-κB)–ras homolog gene family, member A (RhoA)–Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after ovalbumin sensitization and challenge, and the diminished contraction of the tracheal rings in these mice was reversed by IL-17A. These data indicate that the IL-17A produced by TH17 cells contributes to allergen-induced airway hyper-responsiveness through direct effects on airway smooth muscle.
nature.com