MHC class II molecules in B lymphocytes signal through two distinct pathways. The pathway chosen is influenced by the activation status of the cell when class II is ligated. In B cells that have been primed, ligation of MHC class II molecules leads to protein tyrosine kinase (PTK) activation. This is followed by activation of phospholipase C gamma and the generation of the second messengers diacylglycerol and inositol 1,4,5- trisphosphate which mediate PKC activation and mobilization of calcium, respectively. The mechanism by which class II molecules associate with essential effector proteins required for signal transduction is not well understood. Studies have shown that cross-linking of MHC class II molecules on the K46 B lymphoma cell line leads to activation of PTKs and subsequent mobilization of calcium. Variants of this cell line have been generated that lack components of the B cell antigen receptor complex but express wild-type levels of MHC class II. Cross-linking of class II on the variants does not lead to activation of PTKs or mobilization of calcium, even though wild-type levels of key PTKs are expressed. These results suggest that MHC class II may interact with one or more B cell antigen receptor components in order to form a functional signal transduction complex.