| First Author | Zhao FL | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 9 | Pages | 2664-2682 |
| PubMed ID | 30257885 | Mgi Jnum | J:267015 |
| Mgi Id | MGI:6257993 | Doi | 10.4049/jimmunol.1800374 |
| Citation | Zhao FL, et al. (2018) Peroxisome Proliferator-Activated Receptor-delta Supports the Metabolic Requirements of Cell Growth in TCRbeta-Selected Thymocytes and Peripheral CD4(+) T Cells. J Immunol 201(9):2664-2682 |
| abstractText | During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRbeta 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 TCRbeta 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-delta (PPARdelta(mut)) 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 PPARdelta(mut) thymocytes, studies in the OP9-delta-like 4 in vitro system of differentiation revealed that PPARdelta(mut) double-negative 3 cells underwent fewer cell divisions. Naive CD4(+) T cells from PPARdelta(mut) mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-delta-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 PPARdelta(mut) mice. These findings implicate PPAR-delta as a regulator of the metabolic program during thymocyte and T cell growth. |
