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

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.

Decrease in αβ/γδ T‐cell ratio is accompanied by a reduction in high‐fat diet‐induced weight gain, insulin resistance, and inflammation

“…A similar increase in gd T cells was observed in EPI-WAT from HFD-fed TCR-b 2/2 mice (8). This increase might be specific for EPI-WAT because we did not observe it in SC-WAT or in lymphoid tissues (9). The mechanism behind this EPI-WAT-specific increase in gd T cells that accompanies (partial) ab T-cell deficiency remains to be established.…”

“…Tg T-PPAR-b mice that overexpress PPAR-b specifically in T cells were generated by our laboratory as described previously (9). These mice were shown to have impaired ab T-cell development leading to a decrease in ab T cells but no change in gd T-cell number (decrease in ab/ gd T-cell ratio).…”

“…003802; The Jackson Laboratory, Bar Harbor, ME, USA]. Double-Tg animals that overexpress PPAR-b specifically in T cells (Lck-Cre/CAG-Stop-PPAR-b mice), as previously described (9), are referred as Tg T-PPAR-b mice. Male mice (12 wk old) were fed normal chow (NC, 8.4% kcal from fat, A04; Safe Diets, Augy, France) or an HFD (60% kcal from fat; 58Y1; TestDiet, St. Louis, MO, USA) for 17 wk.…”

“…We have previously developed a transgenic (Tg) mouse model that overexpresses the transcription factor peroxisome proliferator-activated receptor b (PPAR-b) specifically in T cells (9). This PPAR-b overexpression inhibits ab T-cell development in the thymus, and as a result these Tg T-PPAR-b mice exhibit an ;70% reduction in ab T cells.…”

“…This PPAR-b overexpression inhibits ab T-cell development in the thymus, and as a result these Tg T-PPAR-b mice exhibit an ;70% reduction in ab T cells. The remaining 30% of ab T cells that manage to develop do not overexpress PPAR-b (9). We used this Tg mouse model to investigate the effect of a partial lack of ab T cells on HFD-induced obesity and its associated inflammation and IR.…”