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

Abstract

IntroductionL-arginine (L-Arg) is a nonessential amino acid that plays a central role in regulating the immune response. 1 In mammalian cells, L-Arg can be catabolized by 4 enzymatic pathways, namely nitric oxide synthase, arginases I and II, arginine:glycine amidinotransferase, and arginine decarboxylase. L-Arg is profoundly reduced in cancer patients, 2 following liver transplantation, 3 or in severe trauma 4 by an increased production of arginase I. This results in a decreased T-cell proliferation and an impaired T-cell function. This effect can be reversed in trauma by the enteral or parenteral supplementation of We demonstrated that activated T cells cultured in medium without L-Arg or cocultured with myeloidderived suppressor cells (MDSCs) isolated from tumors and producing arginase I have a decreased proliferation, a low expression of T-cell receptor CD3 chain, and an impaired production of cytokines. 2,6,7 However, the mechanisms by which L-Arg starvation blocks T-cell proliferation have not been determined.Signaling through the T-cell receptor, as shown by calcium flux and tyrosine phosphorylation, was not affected for the first 12 hours of culture in the absence of L-Arg and therefore could not completely explain the low proliferation of T cells. 8,9 Furthermore, certain T-cell functions such as up-regulation of IL-2 receptor alpha and production of IL-2 were maintained even in the absence of L-Arg. 8,9 Therefore, we explored whether changes in proteins regulating cell cycle could explain the loss of proliferation in T cells cultured without L-Arg. Cyclin-dependent kinase 4 (cdk4) and cyclin-dependent kinase 6 (cdk6) associate with the D-type cyclins, including cyclin D3, to regulate the progression through early G 1 and into the S phase of cell cycle. This regulation requires inactivation of cyclin D/cdk complex inhibitors and phosphorylation of the Rb protein family. Phosphorylation of Rb by cyclin/cdk complexes induces the subsequent release and nuclear translocation of E2F transcription factors, inducing the expression of genes that promote cell-cycle progression into late G 1 and S phases. 10 The effects of amino acid starvation have been well studied in yeast and some tumor cell lines; however, their role in regulating cell cycle in T cells is unknown. The results shown here demonstrate that L-Arg depletion selectively impairs the expression of cyclin D3 and cdk4, blocking the downstream signaling. GCN2, a kinase involved in amino acid starvation, plays a central role in regulating the cell-cycle arrest induced by L-Arg starvation. These results may provide a new understanding of the impairment of the immune response in various diseases where myeloid-derived suppressor cells, producing high levels of arginase, deplete L-Arg. Materials and methods Cells, cultures, and chemicalsHuman peripheral blood mononuclear cells were obtained from healthy donor buffy coats. T cells were purified using human T-cell enrichment columns (R&D systems, Minneapolis, MN), following the vendor's recommendations. T-ce...

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