NK cells have primarily been defined by their ability to kill infected cells, tumor cells and some normal cells expressing low levels of MHC class I molecules. NK cells have also been shown to affect adaptive immune responses by their production of both pro- and anti-inflammatory cytokines. Recently it has been shown that adaptive immune responses can be enhanced or maintained also through direct lymphocyte-lymphocyte interactions. One of these interactions was identified to occur between 2B4 and CD48, where 2B4 acted as a co-stimulatory ligand for both NK cells and T cells. In the current article, we discuss the role of 2B4 in the development of adaptive immune responses and the role of NK-T cell interactions in these responses.