Mitochondrial Priming by CD28

Cell. 2017 Oct 5;171(2):385-397.e11. doi: 10.1016/j.cell.2017.08.018. Epub 2017 Sep 14.

Abstract

T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell 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 T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.

Keywords: CD28; CD8 T cells; Cpt1a; adoptive cellular immunotherapy; costimulation; memory T cells; mir33; mitochondrial cristae remodeling; mitochondrial morphology; spare respiratory capacity.

MeSH terms

  • Animals
  • CD28 Antigens / metabolism*
  • Carnitine O-Palmitoyltransferase
  • Enzyme Inhibitors / pharmacology
  • Epoxy Compounds / pharmacology
  • Humans
  • Interleukin-15 / immunology
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Receptors, Antigen, T-Cell / metabolism
  • Stress, Physiological
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • CD28 Antigens
  • Enzyme Inhibitors
  • Epoxy Compounds
  • Interleukin-15
  • Receptors, Antigen, T-Cell
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase
  • carnitine palmitoyltransferase 1A, human
  • etomoxir