Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15.
IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A(2) (cPLA(2)) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC(+) target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA(2) activation and AA release. Finally, cPLA(2) activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA(2) activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets.
Tang
Fangming
F
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Chen
Zhangguo
Z
Ciszewski
Cezary
C
Setty
Mala
M
Solus
Jason
J
Tretiakova
Maria
M
Ebert
Ellen
E
Han
Jin
J
Lin
Anning
A
Guandalini
Stefano
S
Groh
Veronika
V
Spies
Thomas
T
Green
Peter
P
Jabri
Bana
B
D016718:Arachidonic Acid / Q000378:metabolism; D002446:Celiac Disease / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D015550:Cell Degranulation; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018448:Models, Immunological; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000502:physiology; D015854:Up-Regulation
D019409:Interleukin-15; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell; D016718:Arachidonic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D054510:Phospholipases A2, Cytosolic