TY - JOUR
T1 - Cytosolic PLA 2 is required for CTL- Mediated immunopathology of celiac disease via NKG2D and IL-15
AU - Tang, Fangming
AU - Chen, Zhangguo
AU - Ciszewski, Cezary
AU - Setty, Mala
AU - Solus, Jason
AU - Tretiakova, Maria
AU - Ebert, Ellen
AU - Han, Jin
AU - Lin, Anning
AU - Guandalini, Stefano
AU - Groh, Veronika
AU - Spies, Thomas
AU - Green, Peter
AU - Jabri, Bana
PY - 2009/3/16
Y1 - 2009/3/16
N2 - 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 arachi-donic 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 immuno- pathological conditions and define new therapeutic targets.
AB - 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 arachi-donic 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 immuno- pathological conditions and define new therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=63449087957&partnerID=8YFLogxK
U2 - 10.1084/jem.20071887
DO - 10.1084/jem.20071887
M3 - Article
C2 - 19237603
AN - SCOPUS:63449087957
SN - 0022-1007
VL - 206
SP - 707
EP - 719
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -