Suppression of T-cell functions by human granulocyte arginase.
Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3zeta chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression.
Munder
Markus
M
Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. markus_munder@med.uni-heidelberg.de
Schneider
Henriette
H
Luckner
Claudia
C
Giese
Thomas
T
Langhans
Claus-Dieter
CD
Fuentes
Jose M
JM
Kropf
Pascale
P
Mueller
Ingrid
I
Kolb
Armin
A
Modolell
Manuel
M
Ho
Anthony D
AD
D001119:Arginase / Q000235:genetics / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D006098:Granulocytes / Q000201:enzymology*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D001120:Arginine; D001119:Arginase