T cell cholesterol transport links intestinal immune responses to dietary lipid absorption

The intrinsic pathways that control membrane organization in immune cells and the impact of such pathways on cellular functions are not well defined. Here we show that the nonvesicular cholesterol transporter Aster-A links plasma membrane (PM) cholesterol availability in T cells to immune signaling and systemic metabolism. Aster-A is recruited to the PM during T-cell receptor (TCR) activation, where it facilitates the removal of newly generated “accessible” cholesterol. Loss of Aster-A leads to excess PM cholesterol accumulation, resulting in enhanced TCR nano-clustering and signaling, and in Th17 cytokine production. Furthermore, Aster-A associates with STIM1 and negatively regulates STIM1-dependent calcium flux during activation of mouse and human T cells. Finally, mucosal Th17 response towards commensals is restrained by PM cholesterol remodeling. Ablation of Aster-A in T cells stimulates IL-22 production, which reduces intestinal fatty acid absorption, and confers resistance to diet-induced obesity. These findings delineate a multi-tiered regulatory scheme linking immune cell lipid flux to nutrient absorption and systemic physiology. Overall design: To investigate how Aster-A deficiency regulates T cell function related to intestinal absorption, we fasted Aster-A F/F (WT) or CD4-Cre; Aster-A F/F (AdCD4) mice for 16 h to synchronize metabolic status, and then gavaged with 200 ul olive oil. 2 h later, we isolated CD4 T cells from small intestinal lamina propria and performed mRNA-sequencing. We performed differential gene expression analysis using data obtained from RNA-seq of 3 (WT) and 4 (AdCD4) biological replicates.