2B4 (CD244), a member of the CD2 subset of the immunoglobulin superfamily, is important for stimulating human natural killer (NK) cell cytotoxicity and cytokine production. It is expressed on all NK cells, a subpopulation of T cells, monocytes, basophils and eosinophils. 2B4 interaction with its ligand CD48 regulates NK, T and B lymphocyte functions and thus plays a central role in various immune responses. Previous study indicated a role for AP-1 and Ets in the transcription of the 2B4 gene. In this study we report that stimulation of NK cells through surface 2B4 down-regulates its own expression due to a reduction in the promoter activity at the Ets element. The down-regulation of 2B4 could be a mechanism to attenuate the co-stimulatory signal from 2B4--CD48 interactions.