Human MAIT cells show metabolic quiescence with rapid glucose‐dependent upregulation of granzyme B upon stimulation

Madeleine E Zinser,Chansavath Phetsouphanh,Barbara Kronsteiner,Ayako Kurioka,Chris B Willberg,Susanna J Dunachie,Tianqi Leng,Joachim Hagel,Andrew J Highton,Emanuele Marchi,Paul Klenerman

doi:10.1111/imcb.12020

Abstract

Mucosal‐associated invariant T (MAIT) cells are a well‐characterized innate‐like T cell population abundant in the human liver, peripheral tissues and blood. MAIT cells serve in the first line of defense against infections, through engagement of their T cell receptor, which recognizes microbial metabolites presented on MR1, and through cytokine‐mediated triggering. Typically, they show a quiescent memory phenotype but can undergo rapid upregulation of effector functions including cytolysis upon stimulation. T cells profoundly change their cellular metabolism during their maturation and activation. We sought to determine how MAIT cell metabolism may facilitate both the long‐term memory phase in tissue and the transition to rapid effector function. Here, we show, by flow cytometric metabolism assays and extracellular flux analysis that, despite an effector‐memory profile, human MAIT cells are metabolically quiescent in a resting state comparable to naïve and central memory T cells. Upon stimulation, they rapidly increase uptake of glucose and show a concomitant upregulation of the effector molecules notably granzyme B, which is impaired by inhibition of glycolysis with 2‐deoxyglucose. These findings suggest that MAIT cells share some metabolic characteristics of both resting and effector T cell subsets, with a rapid transition upon triggering. Metabolic programming of this cell type may be of interest in understanding and modulating their function in infectious diseases and cancer.

Highlights

Mucosal-associated invariant T (MAIT) cells constitute a population of innate-like T cells abundant in humans
We performed Gene Set Enrichment Analysis[13] on predefined metabolic gene sets from the KEGG (Kyoto Encyclopedia of Genes and Genomes) database for multiple metabolic pathways including glycolysis and oxidative phosphorylation. This analysis revealed that most metabolic gene sets, including glycolysis and oxidative phosphorylation, are enriched in the control CD161À CD8+ population and only gene transcripts relevant for galactose metabolism were enriched in the CD161++ CD8+ population (Supplementary figure 1a)
These data point toward a differential expression of important key metabolic transcripts in resting CD161++ CD8+ T cells compared to the more heterogeneous population of CD161À CD8+ T cells consisting of CD161À na€ıve (TN: 16.85%; IQR 9.6–25.47%), central memory (TCM: 6.25%; IQR 3.83–8.08%), effector memory (TEM: 24.67%; IQR 16.53–32.98%) and terminally differentiated memory cells (TEMRA: 51.98%; IQR 41.73–58.1%)

Summary

Introduction

Mucosal-associated invariant T (MAIT) cells constitute a population of innate-like T cells abundant in humans They make up to 1–10% of peripheral T cells and up to 50% of hepatic T cells.[1] They are present at mucosal surfaces[2] and have been shown to play important roles in settings of bacterial[3] and viral infection[4] as well as cancer.[5] They express a semi-invariant T cell receptor (Va7.2) on their cellular surface,[6] through which they recognize ligands presented by the nonclassical MHC class Ib molecule MR-1 (MHC-class I related protein 1).[2] MR-1 binds metabolites of the riboflavin metabolism pathway, found in certain bacteria such as Escherichia coli. Innate responses show preferential use of glycolysis and the utilization of the pentose phosphate pathway in acute responses.[12]

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