Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice

KARAP/DAP12 is a transmembrane polypeptide with an intracytoplasmic immunor eceptor tyrosine-based activation motif (ITAM). KARAP/DAP12 is associated w ith several activating cell surface receptors in hematopoietic cells. Here, we report that knockin mice bearing a nonfunctional KARAP/DAP12 ITAM prese nt altered innate immune responses. Although in these mice NK cells are pre sent and their repertoire of inhibitory MHC class I receptors is intact, th e NK cell spectrum of natural cytotoxicity toward tumor cell targets is res tricted. KARAP/DAP12 loss-of-function mutant mice also exhibit a dramatic a ccumulation of dendritic cells in muco-cutaneous epithelia, associated with an impaired hapten-specific contact sensitivity. Thus, despite its homolog y with CD3 zeta and FcR gamma, KARAP/DAP12 plays a specific role in innate immunity, emphasizing the nonredundancy of these ITAM-bearing polypeptides in hematopoietic cells.