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J Immunol. 2018 Nov 1;201(9):2664-2682. doi: 10.4049/jimmunol.1800374. Epub 2018 Sep 26.

Peroxisome Proliferator-Activated Receptor-δ Supports the Metabolic Requirements of Cell Growth in TCRβ-Selected Thymocytes and Peripheral CD4+ T Cells.

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Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.
Princess Margaret Genomics Center, Toronto, Ontario M5G 1L7, Canada.
Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada; and.
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
Women's College Health Research Institute, Toronto, Ontario M5G 1N8, Canada.


During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRβ rearrangement, and defects in genes that regulate this proliferation have a profound effect on thymus cellularity and output. Although the signaling pathways that initiate cell cycling and nutrient uptake after TCRβ selection are understood, less is known about the transcriptional programs that regulate the metabolic machinery to promote biomass accumulation during this process. In this article, we report that mice with whole body deficiency in the nuclear receptor peroxisome proliferator-activated receptor-δ (PPARδmut) exhibit a reduction in spleen and thymus cellularity, with a decrease in thymocyte cell number starting at the double-negative 4 stage of thymocyte development. Although in vivo DNA synthesis was normal in PPARδmut thymocytes, studies in the OP9-delta-like 4 in vitro system of differentiation revealed that PPARδmut double-negative 3 cells underwent fewer cell divisions. Naive CD4+ T cells from PPARδmut mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-δ-deficient thymocytes and peripheral CD4+ T cells correlated with decreases in extracellular acidification rate, mitochondrial reserve, and expression of a host of genes involved in glycolysis, oxidative phosphorylation, and lipogenesis. By contrast, mice with T cell-restricted deficiency of Ppard starting at the double-positive stage of thymocyte development, although exhibiting defective CD4+ T cell growth, possessed a normal T cell compartment, pointing to developmental defects as a cause of peripheral T cell lymphopenia in PPARδmut mice. These findings implicate PPAR-δ as a regulator of the metabolic program during thymocyte and T cell growth.


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