Abstract
The intrinsic pathways that control membrane organization in immune cells and their impact on cellular functions are poorly defined. We found that the nonvesicular cholesterol transporter Aster-A linked plasma membrane (PM) cholesterol availability in CD4 T cells to systemic metabolism. Aster-A was recruited to the PM during T cell receptor (TCR) activation, where it facilitated the removal of accessible cholesterol. Loss of Aster-A increased cholesterol accumulation in the PM, which enhanced TCR nanoclustering and signaling. Aster-A associated with stromal interaction molecule 1 (STIM1) and negatively regulated calcium (Ca(2+)) flux. Aster-A deficiency promoted CD4 T cells to acquire a T helper 17 (T(H)17) phenotype and stimulated interleukin-22 production, which reduced intestinal fat absorption and conferred resistance to diet-induced obesity. These findings delineate how immune cell membrane homeostasis links to systemic physiology.