2B4 was initially discovered on murine NK cells and T cells displaying non-MHC dependent cytotoxicity. Human 2B4 was cloned based on sequence homology with mouse 2B4. Recent evidence suggests that the function of this receptor might be different in the two species. Human 2B4 activates NK cell cytotoxicity and interferon gamma production when engaged by CD48, its ligand, on target cells. This activating function of human 2B4 requires recruitment of the SH2 domain containing molecule, SLAM-associated protein or SAP. In the absence of SAP in human NK cells, as occurs in immature NK cells or NK cells from X-linked lymphoproliferative disorder (XLPD) patients, human 2B4 acts as an inhibitory receptor. In contrast, in vitro and in vivo studies using 2B4-deficient mice suggest that the major function of mouse 2B4 is to inhibit murine NK cell functions when triggered by CD48 on target cells, although there are reports of activating function of murine 2B4. This inhibitory function of murine 2B4 is mediated by EAT-2, ERT and possibly other phosphatases like SHP-1 and SHIP. 2B4-SAP interaction in mouse NK cells might be a low affinity one and might not be physiologically relevant considering the inhibitory function of 2B4. This suggests that mouse and human 2B4 diverged functionally with the evolution of greater affinity between 2B4 and SAP in the human species. We speculate that evolutionary pressure from viral infections, possibly EBV, might have led to the emergence of this association and activating function of 2B4 in humans.
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