T cell cholesterol transport links intestinal immune responses to dietary lipid absorption.
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| Title: | T cell cholesterol transport links intestinal immune responses to dietary lipid absorption. |
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| Authors: | Gao, Yajing, Kennelly, John P., Xiao, Xu, Whang, Emily, Ferrari, Alessandra, Bedard, Alexander H., Mack, Julia J., Nguyen, Alexander, Srikanth, Sonal, Weston, Thomas, Uchiyama, Lauren F., Cohn, Whitaker, Cho, Danielle H., Lee, Min Sub, Whitelegge, Julian, Gwack, Yousang, Young, Stephen G., Bensinger, Steven J., Tontonoz, Peter |
| Source: | Science. 10/9/2025, Vol. 390 Issue 6769, p1-22. 22p. |
| Subjects: | T cells, Cholesterol, Immune response, Lipids in the body, Cell membranes |
| 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 (Ca2+) flux. Aster-A deficiency promoted CD4 T cells to acquire a T helper 17 (TH17) 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. Editor's summary: Cholesterol is an important component of cell membranes and can be shuttled between different subcellular compartments through the action of proteins belonging to the Aster family. Gao et al. found that deleting Aster-A specifically in T cells inhibited the uptake of dietary fats and prevented diet-induced obesity in mice (see the Perspective by Burkhardt and Ecker). By regulating the abundance of cholesterol in the plasma membrane, Aster-A modulated T cell receptor signaling and differentiation. In the absence of Aster-A, CD4 T cells in the gut produced a cytokine, interleukin-22, which decreased the ability of intestinal epithelial cells to take up fatty acids from the diet. —Sarah H. Ross INTRODUCTION: Impaired lipid flux can lead to cellular and tissue dysfunction in human diseases, yet the pathways that maintain membrane lipid homeostasis remain incompletely defined. Immune cells, which must adapt to evolving threats and distinct microenvironments, may be especially reliant on their ability to reorganize membranes for optimal function. The initiation and resolution of immune responses also likely require timely recalibration of the cellular lipid repertoire. Whether and how immune cell membrane homeostasis affects organ function and systemic metabolism are incompletely understood. RATIONALE: Cholesterol is an indispensable lipid component of the mammalian plasma membrane (PM). We previously characterized the Aster family of nonvesicular lipid transporters, which transfer cholesterol from the PM to the endoplasmic reticulum. Despite established links between cholesterol abundance and immune signaling, it is unknown how immune cells fine-tune membrane cholesterol. RESULTS: We traced fatty acid uptake in the small intestine of mice and found that specific deletion of Aster-A in T cells reduced fatty acid absorption and conferred resistance to diet-induced obesity. Loss of Aster-A increased a gene expression signature associated with T helper 17 (TH17) cells among small intestine resident T cells. We found that Aster-A was highly expressed in TH17 cells and was indispensable for maintaining appropriate PM cholesterol levels in this cell type. Using specific cholesterol probes, we determined that T cell receptor (TCR) activation transiently increased the accessible PM cholesterol pool, which recruited Aster-A to restrain excess PM cholesterol accumulation. In the absence of Aster-A, excess PM cholesterol was funneled into a distinct cellular lipid pool, the sphingomyelin-sequestered pool, leading to increased TCR nanoclustering. Consequently, Aster-A–deficient TH17 cells exhibited elevated TCR signaling and effector cytokine [interleukin-17 (IL-17) and IL-22] production. Proximity labeling in T cells revealed an interaction between Aster-A and stromal interaction molecule 1 (STIM1), a core component mediating Ca2+ entry after TCR activation. We found that accessible PM cholesterol was required for TCR-induced Ca2+ influx and that Aster-A dampened this process. Aster-A thus restrained both the early signals directly triggered by the TCR and the later signaling events that depend on Ca2+ influx. Single-cell transcriptomics and immune profiling further pinpointed increased IL-22 levels in TH17 cells from the small intestines of T cell–specific Aster-A–deficient mice. Acute administration of IL-22 before feeding was sufficient to suppress intestinal fatty acid uptake. Conversely, blocking IL-22 with neutralizing antibodies, genetic ablation of Il22 from T cells, or antibiotic depletion of microbial signals that maintain gut TH17 cells each restored dietary fat absorption or diet-induced weight gain. CONCLUSION: Our work identifies a rapid, on-demand regulator of immune membrane homeostasis. Aster-A responds to TCR activation–induced PM remodeling and subsequently removes excess membrane cholesterol to restrain TCR signaling cascades. We propose that membrane lipid remodeling may serve to promote microenvironmental adaptation by controlling tissue T cell reactivity. Dysregulation and accumulation of T cell PM cholesterol therefore has the potential to lead to aberrant gut TH17 effector function, alters immune-epithelial communication, and modulates intestinal and systemic nutrient metabolism. Nonvesicular cholesterol transport links intestinal T cell immunity to lipid absorption.: T cell activation induces PM accumulation of accessible cholesterol and recruits Aster-A, which extracts cholesterol and transfers it to the endoplasmic reticulum to dampen TCR nanoclustering. Aster-A–STIM1 association at the PM further restrains Ca2+ influx during TCR activation (indicated by a lightning bolt). Aster-A guards against excessive intestinal TH17 responses, thereby coordinating dietary lipid flux and systemic metabolism. GRAM, GRAM domain of Aster-A; ORAI1, calcium release-activated calcium modulator 1; TM, transmembrane domain of Aster-A. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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