L-arginine availability regulates T-lymphocyte cell-cycle progression

Blood. 2007 Feb 15;109(4):1568-73. doi: 10.1182/blood-2006-06-031856. Epub 2006 Oct 5.

Abstract

L-arginine (L-Arg) plays a central role in several biologic systems including the regulation of T-cell function. L-Arg depletion by myeloid-derived suppressor cells producing arginase I is seen in patients with cancer inducing T-cell anergy. We studied how L-Arg starvation could regulate T-cell-cycle progression. Stimulated T cells cultured in the absence of L-Arg are arrested in the G0-G1phase of the cell cycle. This was associated with an inability of T cells to up-regulate cyclin D3 and cyclin-dependent kinase 4 (cdk4), but not cdk6, resulting in an impaired downstream signaling with a decreased phosphorylation of Rb protein and a low expression and binding of E2F1. Silencing of cyclin D3 reproduced the cell cycle arrest caused by L-Arg starvation. The regulation of cyclin D3 and cdk4 by L-Arg starvation occurs at transcriptional and posttranscriptional levels. Signaling through GCN2 kinase is triggered during amino acid starvation. Experiments demonstrated that T cells from GCN2 knock-out mice did not show a decreased proliferation and were able to up-regulate cyclin D3 when cultured in the absence of L-Arg. These results contribute to the understanding of a central mechanism by which cancer and other diseases characterized by high arginase I production may cause T-cell dysfunction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arginine / analysis
  • Arginine / deficiency
  • Arginine / physiology*
  • Cell Cycle*
  • Cell Proliferation
  • Clonal Anergy*
  • Cyclin D3
  • Cyclin-Dependent Kinases / genetics
  • Cyclins / genetics
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • Neoplasms / immunology
  • Protein Serine-Threonine Kinases
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / pathology

Substances

  • CCND3 protein, human
  • Ccnd3 protein, mouse
  • Cyclin D3
  • Cyclins
  • Arginine
  • Eif2ak4 protein, mouse
  • Protein Serine-Threonine Kinases
  • Cyclin-Dependent Kinases