한빛사논문
- 조회407
Dongkyun Kim,1,8,* Giha Kim,1,8 Rongzhen Yu,1,8 Juyeun Lee,2,9 Sohee Kim,1 Mia R. Gleason,1 Kevin Qiu,3 Elena Montauti,4,10 Li Lily Wang,5 Deyu Fang,4,7 Jaehyuk Choi,3,7 Navdeep S. Chandel,6,7 Samuel Weinberg,4,7 and Booki Min 1,7,11,*
1Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
3Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
5Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
6Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
7Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
8These authors contributed equally
9Present address: Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
10Present address: Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
11Lead contact
*Corresponding authors: correspondence to Dongkyun Kim or Booki Min
Abstract
Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.
논문정보
- Research article
- 2024년 09월 (BRIC 등록일 2024-09-19)
- 국외 연구진
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