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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2421-2428.
Prepublished online as a Blood First Edition Paper on January 11, 2008; DOI 10.1182/blood-2007-11-123513.
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IMMUNOBIOLOGY
Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF- B and MAPK activation to selectively control cytokine production
Olaf Gross1,*,
Christina Grupp1,*,
Christian Steinberg2,
Stephanie Zimmermann1,
Dominikus Strasser1,
Nicole Hannesschläger1,
Wolfgang Reindl2,
Helena Jonsson3,
Hairong Huo4,
Dan R. Littman4,
Christian Peschel1,
Wayne M. Yokoyama3,
Anne Krug2, and
Jürgen Ruland1
1 III Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany;
2 II Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany;
3 Howard Hughes Medical Institute, Washington University School of Medicine, Rheumatology Division, Department of Medicine, St Louis, MO; and
4 Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine
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- B 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.
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