NFKB1 and X-linked lymphoproliferative disease: Here the authors show that while NKG2D, 2B4, or DNAM-1 receptor activation is insufficient to induce cytokine production, these signals synergize by Vav-1-mediated NF-κB multiphosphorylation, and this signaling checkpoint is defective in X-linked lymphoproliferative disease.