Abstract
T cell receptor (TCR) signaling without CD28 can elicit primary effector Tcells, but memory Tcells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon Tcell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for Tcells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory Tcells. Ourdata show that initial CD28 signals during Tcell activation prime mitochondria with latent metabolic capacity that is essential for future Tcell responses.
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