A role for Peroxisome Proliferator-Activated Receptor Beta in T cell development.

Isabelle Mothe-Satney,Raphaëlle Squillace,Anne-Sophie Rousseau,Joseph Murdaca,Gwenaëlle Le Menn,Frederic Larbret,Paul A Grimaldi,Akila Rekima,Juline Pelé,Jaap G Neels,Valérie Verhasselt,Brigitte Sibille

doi:10.1038/srep34317

Isabelle Mothe-Satney, Raphaëlle Squillace + Show 10 more

Open Access

https://doi.org/10.1038/srep34317

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Abstract

Metabolism plays an important role in T cell biology and changes in metabolism drive T cell differentiation and fate. Most research on the role of metabolism in T lymphocytes focuses on mature T cells while only few studies have investigated the role of metabolism in T cell development. In this study, we report that activation or overexpression of the transcription factor Peroxisome Proliferator-Activated Receptor β (PPARβ) increases fatty acid oxidation in T cells. Furthermore, using both in vivo and in vitro models, we demonstrate that PPARβ activation/overexpression inhibits thymic T cell development by decreasing proliferation of CD4−CD8− double-negative stage 4 (DN4) thymocytes. These results support a model where PPARβ activation/overexpression favours fatty acid- instead of glucose-oxidation in developing T cells, thereby hampering the proliferative burst normally occurring at the DN4 stage of T cell development. As a consequence, the αβ T cells that are derived from DN4 thymocytes are dramatically decreased in peripheral lymphoid tissues, while the γδ T cell population remains untouched. This is the first report of a direct role for a member of the PPAR family of nuclear receptors in the development of T cells.

Highlights

Recent studies have demonstrated the importance of metabolism in T cell biology and how metabolic changes drive T cell differentiation and fate
We have previously shown that PPARβcontrols in myotubes the expression of genes implicated in fatty acid (FA) uptake, handling and catabolism (Fatty Acid Translocase, FAT/CD36; Pyruvate dehydrogenase kinase 4, PDK4; and carnitine palmitoyltransferase 1A, CPT1A) and that in skeletal muscle, PPARβis upregulated in physiological situations characterized by increased lipido-oxidative metabolism, such as fasting or aerobic exercise training[10,11,12]
We subsequently quantified in these cells the relative mRNA levels of a set of 84 genes known to be implicated in fatty acid metabolism using a mouse fatty acid metabolism PCR array

Summary

Introduction

Recent studies have demonstrated the importance of metabolism in T cell biology and how metabolic changes drive T cell differentiation and fate (for recent reviews see refs 1–3). We investigated the effect of overexpressing PPARβon T cell biology in vivo by using mice that overexpress PPARβin a T cell specific manner Using this transgenic mouse model, and by systemic treatment of wild-type mice with a PPARβagonist, we demonstrate that activation/overexpression of PPARβincreases the fatty acid oxidation capacity of developing T cells, thereby inhibiting the proliferative burst at the DN4 stage. This leads to disruption of T cell development in the thymus with subsequent consequences for T cell populations in peripheral lymphoid organs

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