IFN-gamma-dependent and -independent initiation of switch recombination by NK cells.

We have examined the effect of IL-2-propagated NK or NK-T cells on each of the steps required for B cell switch recombination leading to IgG2a production. The results indicate that NK cells, on their own and in the absence of IFN-gamma, can induce germline transcription in resting, IgG(-) B lymphocytes from the gamma2a locus as well as mRNA for activation-induced cytidine deaminase (AID) via a process that requires cell-cell interactions. The results also show that, in contrast to induction by T cells, activation by NK cells does not involve CD40-CD40 ligand interactions and does not extend to the induction of Igamma1 transcription. Furthermore, in contrast to stimulation by LPS and IFN-gamma or by T cells, the activation events initiated by NK cells do not result in significant synthesis of functional gamma2a mRNA in resting B lymphocytes even in the presence of IFN-gamma. Thus, induction of germline and AID transcripts are necessary but not sufficient events for functional switching to IgG2a. These experiments, showing that NK cells themselves cannot induce IgG2a production but can polyclonally program B lymphocytes so that they preferentially switch to this isotype may explain how activated NK cells can skew the Ag-specific immune response toward IgG2a. The findings also provide further demonstration of the definitive yet limited extent of how a non-Ag-specific component of the innate system can modulate the direction of the adaptive immune response.