title: Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15.
abstract: 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.
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Fangming
authors.initials: F
authors.lastname: Tang
authors.forename: Zhangguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Cezary
authors.initials: C
authors.lastname: Ciszewski
authors.forename: Mala
authors.initials: M
authors.lastname: Setty
authors.forename: Jason
authors.initials: J
authors.lastname: Solus
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Ellen
authors.initials: E
authors.lastname: Ebert
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Stefano
authors.initials: S
authors.lastname: Guandalini
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
authors.forename: Peter
authors.initials: P
authors.lastname: Green
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
mesh_terms: 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
chemical_list: 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