2. Academic Validation
  3. Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming

Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming

  • Immunity. 2024 Aug 23:S1074-7613(24)00407-2. doi: 10.1016/j.immuni.2024.08.008.
Dongkyun Kim 1,  Giha Kim 2,  Rongzhen Yu 2,  Juyeun Lee 3,  Sohee Kim 2,  Mia R Gleason 2,  Kevin Qiu 4,  Elena Montauti 5,  Li Lily Wang 6,  Deyu Fang 7,  Jaehyuk Choi 8,  Navdeep S Chandel 9,  Samuel Weinberg 7,  Booki Min 10
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: dongkyun.kim@northwestern.edu.
  • 2 Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 3 Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
  • 4 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 5 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 6 Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
  • 7 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 8 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 9 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 10 Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: booki.min@northwestern.edu.
PMID: 39236718 DOI: 10.1016/j.immuni.2024.08.008
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.

Keywords

Lag3; Myc; Treg cells; autoimmunity; metabolism.

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