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

Yajing Gao; John P Kennelly; Xu Xiao; Emily Whang; Alessandra Ferrari; Alexander H Bedard; Julia J Mack; Alexander Nguyen; Sonal Srikanth; Thomas Weston; Lauren F Uchiyama; Whitaker Cohn; Danielle H Cho; Min Sub Lee; Julian Whitelegge; Yousang Gwack; Stephen G Young; Steven J Bensinger; Peter Tontonoz

doi:10.1126/science.adt4169

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

Science. 2025 Oct 9;390(6769):eadt4169. doi: 10.1126/science.adt4169. Epub 2025 Oct 9.

Authors

Yajing Gao^#^{1

2}, John P Kennelly^#^{1

2}, Xu Xiao^{1

2}, Emily Whang^{1

2

3}, Alessandra Ferrari^{1

2}, Alexander H Bedard^{1

2}, Julia J Mack^{4

5}, Alexander Nguyen^{1

2

6}, Sonal Srikanth⁷, Thomas Weston⁸, Lauren F Uchiyama^{1

2

5}, Whitaker Cohn⁹, Danielle H Cho^{1

2}, Min Sub Lee^{10

11}, Julian Whitelegge⁹, Yousang Gwack⁶, Stephen G Young^{4

7}, Steven J Bensinger^{10

11}, Peter Tontonoz^{1

2

5}

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ The Pasarow Mass Spectrometry Laboratory, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

^# Contributed equally.

PMID: 41066556
DOI: 10.1126/science.adt4169

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 (T_H17) 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.

MeSH terms

Animals
Biological Transport
CD4-Positive T-Lymphocytes* / immunology
CD4-Positive T-Lymphocytes* / metabolism
Calcium / metabolism
Cell Membrane / metabolism
Cholesterol* / metabolism
Dietary Fats* / metabolism
Homeostasis
Interleukin-22
Interleukins / biosynthesis
Interleukins / metabolism
Intestinal Absorption*
Intestinal Mucosa* / immunology
Intestinal Mucosa* / metabolism
Intestines / immunology
Mice
Mice, Inbred C57BL
Obesity / immunology
Obesity / metabolism
Receptors, Antigen, T-Cell / metabolism
Th17 Cells* / immunology

Substances

Cholesterol
Receptors, Antigen, T-Cell
Dietary Fats
Interleukin-22
Interleukins
Calcium

Abstract

MeSH terms

Substances

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