Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice.
Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPgammaS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion.


CONCLUSIONS
We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.
Department of Medicine and Surgery, Liver Center and Transplantation Institute, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Guido
G
Beldi
Yara
Y
Banz
Alexander
A
Kroemer
Xiaofeng
X
Sun
Yan
Y
Wu
Nadine
N
Graubardt
Alyssa
A
Rellstab
Martina
M
Nowak
Keiichi
K
Enjyoji
Xian
X
Li
Wolfgang G
WG
Junger
Daniel
D
Candinas
Simon C
SC
Robson
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000172:deficiency* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018048:Receptors, Purinergic P2 / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*
D015703:Antigens, CD; D018048:Receptors, Purinergic P2; C022571:adenosine 5'-O-(3-thiotriphosphate); D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen