Antigen receptor control of methionine metabolism in T cells.

Linda V Sinclair,Jeffrey C Rathmell,Andrew Jm Howden,Angus I Lamond,Peter M Taylor,Jason W Locasale,Andrew N Macintyre,Sarah Thomson,Doreen A Cantrell,Jens L Hukelmann,Alejandro Brenes,Xiaojing Liu,Laura Spinelli

doi:10.7554/elife.44210

Linda V Sinclair, Jeffrey C Rathmell + Show 11 more

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https://doi.org/10.7554/elife.44210

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Abstract

Immune activated T lymphocytes modulate the activity of key metabolic pathways to support the transcriptional reprograming and reshaping of cell proteomes that permits effector T cell differentiation. The present study uses high resolution mass spectrometry and metabolic labelling to explore how murine T cells control the methionine cycle to produce methyl donors for protein and nucleotide methylations. We show that antigen receptor engagement controls flux through the methionine cycle and RNA and histone methylations. We establish that the main rate limiting step for protein synthesis and the methionine cycle is control of methionine transporter expression. Only T cells that respond to antigen to upregulate and sustain methionine transport are supplied with methyl donors that permit the dynamic nucleotide methylations and epigenetic reprogramming that drives T cell differentiation. These data highlight how the regulation of methionine transport licenses use of methionine for multiple fundamental processes that drive T lymphocyte proliferation and differentiation.

Highlights

IntroductionT lymphocytes responding to antigen undergo rapid proliferation as they differentiate to produce effector populations
T cells need a supply of glucose, leucine and arginine to sustain the activity of the serine/threonine kinase complex Mammalian Target of Rapamycin Complex 1 (Finlay et al, 2012; Nicklin et al, 2009; Wang et al, 2015), a critical kinase that regulates the differentiation and migratory capacity of effector T cells (Delgoffe et al, 2011; Sinclair et al, 2008); serine is required for biosynthesis of purine nucleotides needed for T cell proliferation (Ma et al, 2017)
In these experiments CD4+ T cells were activated by triggering TCR complexes and CD28 and cultured in Interleukin 2 (IL2) and IL12 to differentiate into Th1 cells that produce high levels of interferon gamma (IFNg)

Summary

Introduction

T lymphocytes responding to antigen undergo rapid proliferation as they differentiate to produce effector populations. T cells undergo large-scale, dynamic transcriptional remodelling during differentiation in response to immune activation (Sen et al, 2016; Crompton et al, 2016; Gray et al, 2014; Zhang et al, 2014). Immune activation of T lymphocytes requires that these cells adapt their metabolic programs to support rapid clonal expansion and cell differentiation. Activated T cells accelerate glucose metabolism to fuel oxidative phosphorylation, glycolysis and the production of UDP-GlcNAc to allow critical intracellular protein O-GlcNAcylations (Donnelly and Finlay, 2015; Swamy et al, 2016). Activated T cells dramatically upregulate lipid production programs to meet the demand for membrane biosynthesis associated with growth and proliferation (Kidani et al, 2013). T cells need a supply of glucose, leucine and arginine to sustain the activity of the serine/threonine kinase complex Mammalian Target of Rapamycin Complex 1

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