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The Central Role of Arginine Catabolism in T-Cell Dysfunction and Increased Susceptibility to Infection After Physical Injury

2013; Lippincott Williams & Wilkins; Volume: 259; Issue: 1 Linguagem: Inglês

10.1097/sla.0b013e31828611f8

1528-1140

Xinmei Zhu, John P. Pribis, Paulo C. Rodrı́guez, Sidney M. Morris, Yoram Vodovotz, Timothy R. Billiar, Juan B. Ochoa,

Neonatal Respiratory Health Research

In Brief Objective: To explore the hypothesis that decreased arginine availability by myeloid-derived suppressor cells (MDSCs) is a cause of T-cell dysfunction after physical injury (PI). Background: Arginine is an essential amino acid for normal T-cell function whose availability becomes limited after PI. MDSCs expressing arginase 1 are induced by PI. T-cell dysfunction after PI seems to increase the risk of infection but the mechanisms that cause it are unclear. Methods: PI was created using a standard laparotomy model. Phenotypical and functional alterations in T cells were evaluated in vivo. MDSCs expressing arginase 1 were measured by flow cytometry. Infection after PI was created by intraperitoneal injection of Listeria monocytogenes. Nω-Hydroxy-Nor-L-arginine (Nor-NOHA) was used as an arginase inhibitor. The effect of arginine depletion on T-cell function and susceptibility to infection was assessed through adoptive transfer of MDSC or injection of arginase into noninjured mice. Results: PI caused a decrease in intracellular arginine in T cells, loss of the T-cell receptor (TCR) CD3-ζ chain, inhibition of in vivo T-cell proliferation, memory, and cytotoxicity. PI exponentially increased bacterial growth and mortality to L. monocytogenes. T-cell dysfunction and increased infection were reversed by arginase inhibitor Nor-NOHA but were reproduced by adoptively transferring MDSC or injecting arginase 1 to noninjured mice. Conclusions: Arginine availability is decreased after PI coinciding with an induction of MDSC expressing arginase 1. Decreased arginine may inhibit T-cell function and increase susceptibility to infection after injury. The mechanisms leading to increased susceptibility to infection after injury are poorly understood. This article provides evidence that limitations in arginine availability caused by myeloid cells expressing arginase 1 negatively affect T lymphocyte function after injury and increase susceptibility to infection.