Submitted June 26, 2006
Accepted September 26, 2006
L-Arginine availability regulates T lymphocyte cell cycle progression
Paulo C. Rodriguez*, David G. Quiceno, and Augusto C. Ochoa
Tumor Immunology Program, Stanley S. Scott Cancer Center, Louisiana State University, Health Sciences Center, New Orleans, LA, United States
Dept of Pediatrics, Louisiana State University, Health Sciences Center, New Orleans, LA, United States
* Corresponding author; email: prodri1{at}lsuhsc.edu.
L-Arginine (L-Arg) plays a central role in several biological systems including the regulation of T cell function. L-Arg depletion by myeloid 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 G0-G1 phase of the cell cycle. This was associated with an inability of T cells to upregulate 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 post-transcriptional levels. Signaling through GCN2 kinase is triggered during amino acid starvation. Experiments demonstrated that T cells from GCN2 knockout mice did not show a decreased proliferation and were able to upregulate cyclin D3 when cultured in the absence of L-Arg. These results contribute to understand a central mechanism by which cancer and other diseases characterized by high arginase I production may cause T cell dysfunction.
