Lymphocyte Activation Gene-3 Regulates Dendritic Cell Metabolic Programing and T Cell Priming Function.

Area of Science:

• Immunology
• Cell Biology
• Cardiovascular Research

Background:

• Lymphocyte activation gene-3 (LAG3) deficiency is linked to higher cardiovascular disease risk.
• LAG3-deficient B lymphoblasts show altered cytokine profiles (increased TNF-α, decreased IL-10).

Purpose of the Study:

• To investigate the impact of Lag3 deficiency in dendritic cells (DCs) on cytokine expression, cellular metabolism, and T cell priming.
• To explore the role of Lag3 in DC function and its potential contribution to cardiovascular disease risk.

Main Methods:

• Murine bone marrow-derived DCs (BMDCs) were used to analyze cytokine secretion, cellular metabolism, and gene/protein expression via RNA sequencing and proteomics.
• Adoptive transfer of OT-II CD4+ T cells into wild-type and Lag3-deficient mice, along with ex vivo splenocyte analysis.
• In vitro BMDC:T cell coculture experiments.

Main Results:

• Lag3-deficient BMDCs secreted more TNF-α, exhibited increased glycolysis, and reduced fatty acid utilization for mitochondrial respiration.
• RNA sequencing and proteomics revealed altered expression of immune-related genes/proteins in Lag3-deficient BMDCs, including CD40 and CD86.
• Lag3-deficient DCs promoted greater T cell effector differentiation and proliferation, with higher IFN-γ production observed ex vivo.

Conclusions:

• Lag3 deficiency in DCs is associated with a pro-inflammatory phenotype.
• This inflammatory phenotype in DCs provides a potential mechanism linking LAG3 deficiency to increased cardiovascular disease risk in humans.