Mitochondrial Pyruvate Carrier 1 Promotes Peripheral T Cell Homeostasis through Metabolic Regulation of Thymic Development

Cell Rep. 2020 Mar 3;30(9):2889-2899.e6. doi: 10.1016/j.celrep.2020.02.042.

Abstract

Metabolic pathways regulate T cell development and function, but many remain understudied. Recently, the mitochondrial pyruvate carrier (MPC) was identified as the transporter that mediates pyruvate entry into mitochondria, promoting pyruvate oxidation. Here we find that deleting Mpc1, an obligate MPC subunit, in the hematopoietic system results in a specific reduction in peripheral αβ T cell numbers. MPC1-deficient T cells have defective thymic development at the β-selection, intermediate single positive (ISP)-to-double-positive (DP), and positive selection steps. We find that early thymocytes deficient in MPC1 display alterations to multiple pathways involved in T cell development. This results in preferred escape of more activated T cells. Finally, mice with hematopoietic deletion of Mpc1 are more susceptible to experimental autoimmune encephalomyelitis. Altogether, our study demonstrates that pyruvate oxidation by T cell precursors is necessary for optimal αβ T cell development and that its deficiency results in reduced but activated peripheral T cell populations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anion Transport Proteins / deficiency
  • Anion Transport Proteins / metabolism*
  • Gene Deletion
  • Glycolysis
  • Hematopoiesis
  • Homeostasis*
  • Humans
  • Inflammation / pathology
  • Jurkat Cells
  • Lymphocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Membrane Transport Proteins / deficiency
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Monocarboxylic Acid Transporters / deficiency
  • Monocarboxylic Acid Transporters / metabolism*
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Pyruvic Acid / metabolism
  • T-Lymphocytes / metabolism*
  • Thymocytes / metabolism
  • Thymus Gland / growth & development*
  • Thymus Gland / metabolism*

Substances

  • Anion Transport Proteins
  • MPC1 pyruvate carrier protein, mouse
  • Mitochondrial Membrane Transport Proteins
  • Monocarboxylic Acid Transporters
  • Pyruvic Acid