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Modulation of T cell function through L-arginine metabolism: a new therapy from an old enemy
  1. Matthew Fletcher1,3,
  2. Maria E Ramirez1,
  3. Rosa Sierra1,
  4. Patrick Raber1,2 and
  5. Paulo Rodriguez1,2
  1. Aff1 grid.279863.10000000089541233Stanley S. Scott Cancer CenterLouisiana State University Health Sciences Center New Orleans LA USA
  2. Aff2 grid.279863.10000000089541233Department of Microbiology, Immunology and ParasitologyLouisiana State University Health Sciences Center New Orleans LA USA
  3. Aff3 grid.279863.10000000089541233Department of PediatricsLouisiana State University Health Sciences Center New Orleans LA USA

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Meeting abstracts

Recent studies have suggested the relevance of different energy metabolic pathways in the balance between protective T cell immunity and T cell anergy in tumors. We and others have suggested the role of the depletion of the non-essential amino acid L-arginine as a mechanism for the induction of T cell suppression in tumors. Therefore, we hypothesize that it is possible to metabolically regulate T cell responses simply through the modulation of L-arginine. In this study, we aimed to determine the effect of a pegylated form of the human L-arginine-metabolizing enzyme arginase I (peg-Arg I) in T cell responses. Activation of antigen-specific CD4+ and CD8+ T cells in the presence of peg-Arg I prevented cell proliferation and production of IFNγ in vitro and in vivo. Similarly, peg-Arg I impaired proliferation and IFNγ production in T cells activated with PMA/Ionomycin, suggesting that the effect of peg-Arg I was independent of T cell receptor (TCR) signaling. In fact, the anti-proliferative effect induced by peg-Arg I correlated with an arrest of T cells in the G0-G1 phase of the cell cycle, a decreased expression of cyclin D3 and cdk4, and a major inhibition of de novo translation. Interestingly, treatment of T cells with peg-Arg I did not impair the expression of activation markers CD25, CD69, and the production of IL-2, which correlated with an intact mitochondrial biogenesis. As a result, peg-Arg I did not have an effect in oxygen consumption (OCR) by mitochondrial respiration, but significantly blocked glycolytic pathways in activated T cells. Furthermore, peg-Arg I treated T cells increased the expression of genes associated with integrated stress responses (IRS) and arrest in translation including GCN2, Chop, and Atf4. In fact, GCN2 was a major mediator of the effects induced by peg-Arg I. Then, we tested the effect of peg-Arg I in mouse models of graft versus host disease (GVHD) and inflammatory bowel disease (IBD), both mediated through activated T cells. Peg-Arg I significantly extended the survival of mice in these 2 disease models, which associated with a decreased production of IFNγ. Altogether the results suggest the potential effect of the modulation of the metabolism of L-arginine as a mean to modulate T cell responses. Continuation of this study will advance in the understanding of the metabolic effects of L-arginine in T cell function, which could enable the development of therapies to modulate T cell responses in transplantation or autoimmunity.