De novo fatty acid synthesis in invariant NKT cells is critical for the development of airway hyperresponsiveness

Allergic responses in airway against house dust mites (HDMs) depend on lipid metabolism. However, whether the state of lipid metabolism in iNKT cells serves as a critical mechanism to impact development of allergic asthma remains elusive. Here, we showed that acetyl-CoA-Carboxylase 1 (ACC1), a key enzyme for fatty acid synthesis, was highly expressed in iNKT cells from asthmatic lungs. In ovalbumin (OVA)- and HDM-induced allergic asthma models, Cd4-CreAcc1fl/fl mice exhibited impaired homeostasis of iNKT cells and failed to develop AHR. ACC1-deficient iNKT cells reduced intracellular lipid concentration and expression of fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptor-gamma (PPAR-?), whereas these cells were increased in glycolytic capacity. Moreover, ACC1-FABP-PPAR-? axis regulated cell death of ACC1-deficient iNKT cells. Adoptive transfer of wild type (WT) iNKT cells restored AHR in J?18 knockout mice in OVA or HDM-induced asthma models, whereas that of ACC1-deficient iNKT cells did not, indicating that fatty acid synthesis in iNKT cells is one of main contributors to the development of AHR. Our finding demonstrate fatty acid metabolism in iNKT cells is critical contributor for the development of AHR and airway inflammation in asthma. Overall design: Comparative gene expression profiling analysis of RNA-seq data for iNKT cells from ACC1f/f (WT) mice and ACC1f/fCD4cre (KO) mice