Episodes of infection have been postulated to be one of the initiating events of autoimmunity often reflected in dysregulated B cell activity. NK cells are rapidly activated during infection and may therefore contribute to these initiating events. The Sle1 locus, derived from the NZW1410 genome, which is directly related to the spontaneous production of autoantibodies, contains allelic forms of the genes encoding CD244 and CD48. We have found that the expression the receptor CD48 on B cells and its ligands on NK cells is crucial for the direct cell-cell interaction needed for the NK cell induction of partial B cell differentiation as reflected by the initiation of germline transcription necessary for isotype switching. Whereas direct interactions with NK cells do not induce terminal differentiation of B cells, NK cells can, however, also, potentiate the antigen-presenting ability of B cells. Experiments are proposed to investigate the coreceptors that must be involved in signaling by CD48 because it is a GPI-linked protein with no signaling ability on its own. Conversely, B cells can also induce NK cell differentiation via direct cell-cell interactions, as represented by the upregulation of IFN-? secretion as well as the induction of IL-13 mRNA expression. Interestingly, induction of NK-cell IL-13 mRNA expression, requires the ligation of the CD244 receptor, also encoded in the Sle1 locus. The ability of CD244 to function as an activating rather than an inhibitory receptor in this context may also depend on costimulatory molecules expressed on subsets of B cells. Experiments are proposed to dissect the signaling pathways involved in these two opposing events mediated by the same receptor. Further understanding of how the interaction between this receptor/ligand pair impacts NK-B cell interactions may yield important insights into the mechanisms regulating autoantibody production in this strain. To facilitate these studies, we also have, in hand, a transgenic mouse strain that is chronically depleted of only NK cells. This strain will be utilized to dissect the role of NK cells in the spontaneous development of autoimmune disease symptoms and to investigate the in vivo effects of NK potentiation of antigen presentation by B cells which may result in the alteration of the isotype distribution of autoantibodies. ? ? ? ?
