Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease

J Pharmacol Exp Ther. 2014 Nov;351(2):298-307. doi: 10.1124/jpet.114.218099. Epub 2014 Aug 14.


T-cell activation requires increased ATP and biosynthesis to support proliferation and effector function. Most models of T-cell activation are based on in vitro culture systems and posit that aerobic glycolysis is employed to meet increased energetic and biosynthetic demands. By contrast, T cells activated in vivo by alloantigens in graft-versus-host disease (GVHD) increase mitochondrial oxygen consumption, fatty acid uptake, and oxidation, with small increases of glucose uptake and aerobic glycolysis. Here we show that these differences are not a consequence of alloactivation, because T cells activated in vitro either in a mixed lymphocyte reaction to the same alloantigens used in vivo or with agonistic anti-CD3/anti-CD28 antibodies increased aerobic glycolysis. Using targeted metabolic (13)C tracer fate associations, we elucidated the metabolic pathway(s) employed by alloreactive T cells in vivo that support this phenotype. We find that glutamine (Gln)-dependent tricarboxylic acid cycle anaplerosis is increased in alloreactive T cells and that Gln carbon contributes to ribose biosynthesis. Pharmacological modulation of oxidative phosphorylation rapidly reduces anaplerosis in alloreactive T cells and improves GVHD. On the basis of these data, we propose a model of T-cell metabolism that is relevant to activated lymphocytes in vivo, with implications for the discovery of new drugs for immune disorders.

Publication types

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

MeSH terms

  • Animals
  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • Citric Acid Cycle / immunology
  • Female
  • Glutamine / metabolism
  • Glycolysis / immunology
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / metabolism
  • Isoantigens / immunology*
  • Lymphocyte Activation / immunology*
  • Mice
  • Oxidative Phosphorylation
  • Ribose / biosynthesis
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*


  • CD28 Antigens
  • CD3 Complex
  • Isoantigens
  • Glutamine
  • Ribose