The signaling lymphocyte activation molecule (SLAM) family receptor, 2B4/CD244, was first implicated in anti-viral immunity by the discovery that mutations of the SLAM-associated protein, SAP/SH2D1A, impaired 2B4-dependent stimulation of T and natural killer (NK) cell anti-viral functions in X-linked lymphoproliferative syndrome patients with uncontrolled Epstein–Barr virus infections. Here, CD244 is linked to X-linked lymphoproliferative disease.