Human Mucosal Associated Invariant T cell proliferation is dependent on a MYC-SLC7A5-Glycolysis metabolic axis

Abstract

Mucosal Associated Invariant T (MAIT) cells are an abundant population of innate T cells which recognise bacterial ligands presented by the MHC class-I like molecule MR1. MAIT cells play a key role in host protection against bacterial and viral pathogens. Upon activation MAIT cells undergo proliferative expansion and increased production of effector molecules such as cytokines. The molecular and metabolic mechanisms controlling MAIT cell effector functions are still emerging. In this study, we found that expression of the key metabolism regulator and transcription factor MYC is upregulated in MAIT cells upon immune stimulation. Using quantitative mass spectrometry, we identified the activation of two MYC controlled metabolic pathways; amino acid transport and glycolysis, both of which are critical for MAIT cell proliferation. Finally, we show that MYC expression in response to immune activation is diminished in MAIT cells isolated from people with obesity, resulting in defective MAIT cell proliferation and functional responses. Collectively our data details for the first time the importance of MYC regulated metabolism for MAIT cell proliferation, and provides additional insight into the molecular defects underpinning functional failings of MAIT cells in obesity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/476571v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@29d1bforg.highwire.dtl.DTLVardef@1896004org.highwire.dtl.DTLVardef@1febefdorg.highwire.dtl.DTLVardef@1ad0754_HPS_FORMAT_FIGEXP M_FIG C_FIG