Costimulation via the co-receptor CD28 is required for the generation of effective memory T cells. A lack of CD28 signaling during the priming of naive T cells results in anergic T cells that fail to provide protection against subsequent challenge. In Cell, Pearce and colleagues reveal that CD28 signals at initial priming lead to metabolic changes that result in the increased mitochondrial morphology, spare respiratory capacity and fatty-acid metabolism necessary for effector memory responses. Mechanistically, CD28 transiently suppresses the metabolic regulator TXNIP, which regulates expression of the microRNA miR-33. In turn, CD28 enhances expression of the miR-33 target Cpt1a, which encodes the rate-limiting mitochondrial enzyme carnitine palmitoyltransferase that is necessary for fatty-acid oxidation. Modulation of miR-33 expression during T cell priming is inversely correlated with memory-cell function after recall challenge. The Cpt1a inhibitor etomoxir likewise impairs the CD28-dependent function of memory T cells. Thus, early CD28 signals prepare T cells for subsequent memory responses by enhancing mitochondrial capacity and fatty-acid utilization.

Cell (14 September 2017) doi:10.1016/j.cell.2017.08.018