title: The central role of arginine catabolism in T-cell dysfunction and increased susceptibility to infection after physical injury.
abstract: 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. N-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.
authors.affiliation: Departments of *Surgery †Departments of Microbiology, Immunology, and Parasitology, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA. ‡Immunology §Microbiology and Molecular Genetics ¶Critical Care Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA; and ‖Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhu
authors.forename: John P
authors.initials: JP
authors.lastname: Pribis
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Juan B
authors.initials: JB
authors.lastname: Ochoa
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis*; D001120:Arginine / Q000096:biosynthesis*; D004195:Disease Models, Animal; D008088:Listeriosis / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014947:Wounds and Injuries / Q000276:immunology* / Q000503:physiopathology
chemical_list: D001120:Arginine; D001119:Arginase