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

During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCR beta 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 TCR beta 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 (PPAR delta(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 PPAR delta(mut) thymocytes, studies in the OP9-delta-like 4 in vitro system of differentiation revealed that PPAR delta(mu)(t) double-negative 3 cells underwent fewer cell divisions. Naive CD4(+) T cells from PPAR delta(mu)(t) 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 PPAR delta(mu)(t) mice. These findings implicate PPAR-delta as a regulator of the metabolic program during thymocyte and T cell growth.