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¹ Department of Pathology, ² Department of Pediatrics, ³ Ben May Institute for Cancer Research, and ⁴ Department of Medicine, University of Chicago, Chicago, IL 60637
⁵ Department of Medicine, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903
⁶ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
⁷ Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032

CORRESPONDENCE Bana Jabri: bjabri{at}bsd.uchicago.edu

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 A₂ (cPLA₂) 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 cPLA₂ activation and AA release. Finally, cPLA₂ activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA₂ 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.

Abbreviations used: AA, arachidonic acid; BLT, benzyloxycarbonyl lysine thiobenzyl; COX, cyclooxygenase; cPLA₂, cytosolic phospholipase A2; ERK, extracellular signal–regulated kinase; IE-CTL, intraepithelial CTL; ITAM, immunoreceptor tyrosine-based activation motifs; JNK, c-Jun N-terminal kinase; LA, linoleic acid; MIC, MHC class I–related chain; PI3-K, phosphatidylinositol 3-kinase; PB-CTL, peripheral blood CTL; siRNA, small interfering RNA; ULPB, UL-16–binding protein.

© 2009 Tang et al.
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