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

Blood. 2008 Sep 15;112(6):2421-8. doi: 10.1182/blood-2007-11-123513. Epub 2008 Jan 11.


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-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins / metabolism*
  • Caspases / metabolism*
  • Cytokines / biosynthesis
  • Killer Cells, Natural
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Multiprotein Complexes
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / metabolism*
  • Receptors, KIR / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • Card11 protein, mouse
  • Cytokines
  • Multiprotein Complexes
  • NF-kappa B
  • Neoplasm Proteins
  • Receptors, KIR
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein