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

Abstract

Invariant natural-killer T (<i>i</i>NKT) 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 in <i>i</i>NKT cells is very limited. It is also not clear whether such metabolic regulation of <i>i</i>NKT cells could participate in their pathogenic activities in asthma. Here, we showed that acetyl-coA-carboxylase 1 (ACC1)-mediated de novo fatty-acid synthesis is required for the survival of <i>i</i>NKT cells and their deleterious functions in allergic asthma. ACC1, which is a key fatty-acid synthesis enzyme, was highly expressed by lung <i>i</i>NKT cells from WT mice that were developing asthma. <i>Cd4</i>-Cre::<i>Acc1</i>^fl/fl mice failed to develop OVA-induced and HDM-induced asthma. Moreover, <i>i</i>NKT cell-deficient mice that were reconstituted with ACC1-deficient <i>i</i>NKT cells failed to develop asthma, unlike when WT <i>i</i>NKT cells were transferred. ACC1 deficiency in <i>i</i>NKT cells associated with reduced expression of fatty acid-binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR)γ, but increased glycolytic capacity that promoted <i>i</i>NKT-cell death. Furthermore, circulating <i>i</i>NKT cells from allergic-asthma patients expressed higher <i>ACC1</i> and <i>PPARG</i> levels than the corresponding cells from non-allergic-asthma patients and healthy individuals. Thus, de novo fatty-acid synthesis prevents <i>i</i>NKT-cell death via an ACC1-FABP-PPARγ axis, which contributes to their homeostasis and their pathogenic roles in allergic asthma.