Triggering of SLAM-family receptors by heterotypic or homotypic cell–cell interactions. All SLAM-family receptors, except 2B4, are self-ligands. In the case of 2B4, the ligand is CD48, another receptor expressed on hematopoietic cells. Consequently, SLAM-family receptors can be triggered during heterotypic or homotypic cell–cell interactions. (A) Heterotypic cell–cell interactions. Triggering of 2B4 on natural killer cells (NK) by CD48 on target cells results in SAP family adaptor-dependent signals, which enhance cytotoxicity and interferon (IFN)-γ secretion induced through stimulation of the primary activating receptor NKG2D by its ligand Rae-1. (B) Homotypic cell–cell interactions. Triggering of Ly108 by Ly108 on two double-positive thymocytes (DP) results in SAP-dependent signals, which promote positive selection and/or proliferation of DP expressing the appropriate T cell receptor (TCR) and engaged by self-lipid-loaded CD1d.