title: Regulation of NK cell function by human granulocyte arginase.
abstract: The arginine-hydrolyzing enzyme arginase is constitutively expressed by human polymorphonuclear granulocytes (PMN). Upon PMN cell death arginase is liberated and depletes arginine in the microenvironment. This amino acid depletion suppresses T cell proliferation and cytokine secretion and emerges as a key mechanism of immunosuppression during chronic inflammation and tumor growth. Here we show that PMN arginase also severely impairs key functions of primary human NK cells as well as IL-2-activated NK cells. In the absence of arginine, NK cell proliferation and IL-12/IL-18-induced secretion of IFN-gamma are severely diminished. In contrast, NK cell viability, granule exocytosis, and cytotoxicity are independent of extracellular arginine. The mechanism of NK cell suppression by arginine depletion is posttranscriptional since mRNA transcript frequency is unaffected upon NK cell activation in the absence of arginine. Finally, we demonstrate that human purulent exudate ex vivo inhibits NK cell functions exclusively due to liberated arginase. Arginase inhibitors are therefore promising pharmacological agents to treat unwanted suppression of the innate (NK cell) as well as the adaptive (T cell) immune system.
authors.affiliation: Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Oberlies
authors.forename: Carsten
authors.initials: C
authors.lastname: Watzl
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Claudia
authors.initials: C
authors.lastname: Luckner
authors.forename: Pascale
authors.initials: P
authors.lastname: Kropf
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: Markus
authors.initials: M
authors.lastname: Munder
mesh_terms: D001119:Arginase / Q000502:physiology*; D001120:Arginine / Q000172:deficiency / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005089:Exocytosis / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D007165:Immunosuppression Therapy; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D006131:Growth Inhibitors; D001120:Arginine; D001119:Arginase