L-arginine availability regulates T-lymphocyte cell-cycle progression.
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.
Rodriguez
Paulo C
PC
Tumor Immunology Program, Stanley S. Scott Cancer Center, Lousiana State University Health Sciences Center, Department of Pediatrics, New Orleans 70112, USA. prodri1@lsuhsc.edu
Quiceno
David G
DG
Ochoa
Augusto C
AC
D000818:Animals; D001120:Arginine / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D002453:Cell Cycle; D049109:Cell Proliferation; D017635:Clonal Anergy; D056743:Cyclin D3; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology; D017346:Protein Serine-Threonine Kinases; D013601:T-Lymphocytes / Q000166:cytology* / Q000473:pathology
C534696:CCND3 protein, human; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D016213:Cyclins; D001120:Arginine; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases