Antigen receptor control of methionine metabolism in T cells

Linda V. Sinclair (Lead / Corresponding author), Andy Howden, Alejandro Brenes Murillo, Laura Spinelli, Jens Hukelmann, Andrew N. Macintyre, Xiaojing Liu, Sarah Thomson, Peter Taylor, Jeffrey C. Rathmell, Jason W Locasale, Angus Lamond, Doreen A. Cantrell (Lead / Corresponding author)

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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.

Original languageEnglish
Article numbere44210
Pages (from-to)1-29
Number of pages29
JournaleLife
Volume8
DOIs
Publication statusPublished - 27 Mar 2019

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