Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-κB and MAPK activation to selectively control cytokine production

• Published in: Blood 2008-09, Vol.112 (6), p.2421-2428
• Main Authors: Gross, Olaf, Grupp, Christina, Steinberg, Christian, Zimmermann, Stephanie, Strasser, Dominikus, Hannesschläger, Nicole, Reindl, Wolfgang, Jonsson, Helena, Huo, Hairong, Littman, Dan R., Peschel, Christian, Yokoyama, Wayne M., Krug, Anne, Ruland, Jürgen
• Format: Article
• Language: English
• Subjects: Immunobiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-11-123513

Natural killer (NK) cells are innate immune cells that mediate resistance against viruses and tumors. They express multiple activating receptors that couple to immunoreceptor tyrosine-based activation motif (ITAM)–containing signaling chains for downstream cell activation. Ligation of activating NK-cell receptors induces NK-cell cytotoxicity and cytokine release. How these distinct events are selectively controlled is not well defined. Here we report the identification of a specific signaling pathway that operates downstream of the ITAM-coupled NK-cell receptors NK1.1, Ly49D, Ly49H, and NKG2D. Using primary NK cells from Bcl10−/−, Malt1−/−, Carma1−/−, and Card9−/− mice, we demonstrate a key role for Bcl10 signalosomes in the activation of canonical NF-κB signaling as well as JNK and p38 MAPK upon NK-cell triggering. Bcl10 directly cooperates with Malt1 and depends on Carma1 (Card11) but not on Card9 for NK-cell activation. These Bcl10-dependent cascades selectively control cytokine and chemokine production but do not affect NK-cell differentiation or killing. Thus, we identify a molecular basis for the segregation of NK-cell receptor–induced signals for cytokine release and target cell killing and extend the previously recognized roles for CARD-protein/Bcl10/Malt1 complexes in ITAM receptor signaling in innate and adaptive immune cells.