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 “accessible” cholesterol. Loss of Aster-A leads to PM cholesterol
accumulation, resulting in enhanced TCR nano-clustering and signaling, and
Th17 cytokine production. Furthermore, Aster-A associates with STIM1 and
negatively regulates STIM1-dependent Ca2+ 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.