Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15.

Publication Type:

Journal Article

Source:

The Journal of experimental medicine, Volume 206, Issue 3, p.707-19 (2009)

Keywords:

2009, Arachidonic Acid, Celiac Disease, Cell Degranulation, Center-Authored Paper, Clinical Research Division, Cytotoxicity, Immunologic, Enzyme Activation, Epithelial Cells, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry Core Facility, Humans, Interleukin-15, JNK Mitogen-Activated Protein Kinases, Models, Immunological, NK Cell Lectin-Like Receptor Subfamily K, Phospholipases A2, Cytosolic, PHOSPHORYLATION, Receptors, Antigen, T-Cell, Shared Resources, Signal Transduction, T-Lymphocytes, Cytotoxic, Up-Regulation

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.