In addition to the well-documented effect of NK cells on B cell differentiation via their ability to secrete IFN-gamma, NK cells can also induce, via direct cell-cell interactions, germline transcripts (Igamma2a) necessary for switch recombination to IgG2a. Analysis of the ligand-receptor pairs that could be involved in this induction revealed that the expression of CD48 on B cells is crucial for the induction. NK cells from mice with targeted deletions of either the CD2 or the CD244 gene, both of which encode ligands for CD48, are compromised in their ability to induce B cell Igamma2a expression. Interestingly, although CD244 can bind to CD48 with a higher affinity, the ability of NK cells from CD244(-/-) mice to stimulate Igamma2a is not as compromised as NK cells from CD2(-/-) mice. Despite the difference between cell surface receptors that are stimulated by NK cells vs those stimulated by the combination of LPS and IFN-gamma, we show in this study that the initiation of gamma2a germline transcription is regulated by similar cis-acting elements located at the 3' end of the IgH locus. However, NK cells cannot induce the final steps of switch recombination resulting in the production of mature mRNA from recombined DNA. Our findings suggest that these different signaling pathways converge on regulatory elements that are common to germline transcription; however, because NK induction does not result in the final steps of switch recombination, some signals initiated by LPS plus IFN-gamma are not induced by NK cells.