MassIVE MSV000096546

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IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation

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Description

Homeostatic proliferation, driven by cytokines including IL-7, maintains stable T cell populations over time and expands these during lymphopenia, for example following stem cell transplantation. Yet, impaired T cell expansion in this context is associated with diminished immune protection, whilst excessive proliferation contributes to graft versus host disease. This highlights the need to understand molecular mechanisms regulating this process. Here, we studied the metabolic basis for IL-7-driven CD4+ T cell proliferation. We observed that IL-7 promotes glucose uptake and metabolism, including usage for nucleotide synthesis and oxidation in the tricarboxylic acid (TCA) cycle. Of note, contrary to other TCA metabolites, glucose-derived citrate does not accumulate in IL-7 treated cells, indicating diversion into other processes. In agreement, IL-7 promotes glucose-dependent histone acetylation and chromatin accessibility during proliferation. This is particularly notable at gene loci of the amino acid-sensing Ragulator complex. Consistently, expression of its subunit LAMTOR5 is promoted by IL-7 in a glucose-dependent manner. Functionally, glucose availability determined amino acid-dependent mTOR activation in CD4+ T cells, confirming integrated sensing of these nutrients. LAMTOR5 deletion impaired IL-7-mediated CD4+ T cell expansion, establishing that glycolysis in absence of Ragulator activation was insufficient to initiate this process. Clinically, CD4+ T cells isolated from patients following myeloablative autologous stem cell transplantation demonstrate coordinated upregulation of genes encoding glycolytic and TCA cycle enzymes, as well as amino acid sensing machinery and mTOR targets. Our findings uncover integrated sensing of glucose and amino acid metabolism and demonstrate its relevance during homeostatic T cell proliferation. [doi:10.25345/C5222RJ4S] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: CD4 T-cell, homeostatic proliferation, metabolism ; DatasetType:Metabolomics

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Principal Investigators:
(in alphabetical order) 		Sarah Dimeloe, University of Birmingham, United Kingdom
Submitting User: alejandro_metabo10
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