The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors

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Abstract
Immunoreceptor tyrosine-based activation motifs (ITAMs) are crucial in antigen receptor signaling in acquired immunity. Although receptors associated with the ITAM-bearing adaptors FcRγ and DAP12 on myeloid cells have been suggested to activate innate immune responses, the mechanism coupling those receptors to 'downstream' signaling events is unclear. The CARMA1–Bcl-10–MALT1 complex is critical for the activation of transcription factor NF-κB in lymphocytes but has an unclear function in myeloid cells. Here we report that deletion of the gene encoding the Bcl-10 adaptor–binding partner CARD9 resulted in impaired myeloid cell activation of NF-κB signaling by several ITAM-associated receptors. Moreover, CARD9 was required for Toll-like receptor–induced activation of dendritic cells through the activation of mitogen-activated protein kinases. Although Bcl10−/− and Card9−/− mice had similar signaling impairment in myeloid cells, Card11−/− (CARMA1-deficient) myeloid cell responses were normal, and although Card11−/− lymphocytes were defective in antigen receptor–mediated activation, Card9−/− lymphocytes were not. Thus, the activation of lymphoid and myeloid cells through ITAM-associated receptors or Toll-like receptors is regulated by CARMA1–Bcl-10 and CARD9–Bcl-10, respectively.