De novofatty-acid synthesis protects invariant NKT cells from cell death, thereby promoting their homeostasis and pathogenic roles in airway hyperresponsiveness

Invariant natural-killer T (iNKT) cells play pathogenic roles in allergic asthma in murine models and possibly also humans. While many studies show that the development and functions of innate and adaptive immune cells depend on their metabolic state, the evidence for this iniNKT cells is very limited. It is also not clear whether such metabolic regulation ofiNKT cells could participate in their pathogenic activities in asthma. Here, we showed that acetyl-coA-carboxylase 1 (ACC1)-mediatedde novofatty-acid synthesis is required for the survival ofiNKT cells and their deleterious functions in allergic asthma. ACC1, which is a key fatty-acid synthesis enzyme, was highly expressed by lungiNKT cells from WT mice that were developing asthma.Cd4-CreAcc1^fl/flmice failed to develop OVA-induced and HDM-induced asthma. Moreover,iNKT cell-deficient mice that were reconstituted with ACC1-deficientiNKT cells failed to develop asthma, unlike when WTiNKT cells were transferred. ACC1 deficiency iniNKT cells associated with reduced expression of fatty acid-binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR)γ, but increased glycolytic capacity that promotediNKT-cell death. Furthermore, circulatingiNKT cells from allergic-asthma patients expressed higherACC1andPPARGlevels than the corresponding cells from non-allergic-asthma patients and healthy individuals. Thus,de novofatty-acid synthesis preventsiNKT-cell deathviaan ACC1-FABP-PPARγ axis, which contributes to their homeostasis and their pathogenic roles in allergic asthma.