gamma 1 heavy chain transgenes are responsive to IFN- gamma repression and CD40 ligation

The cis-acting elements that regulate production of germ-line transcripts from Ig heavy chain genes and subsequent switch recombination to those genes are poorly defined. We reported that a 17-kb transgene that includes I gamma 1, S gamma 1, and C gamma 1 is regulated for germ-line transcription like the endogenous gamma 1 gene. Transcripts from such transgenes are expressed only in B cells treated with both LPS and IL-4, and not in B cells treated with LPS alone or in thymocytes or nonlymphoid tissues. We have now found that transcripts from these transgenes are induced by treatment of transgenic B cells by IL-4 alone. As reported by others, IFN- gamma acts to inhibit the IL-4-mediated induction of germ-line transcripts of the endogenous gamma 1 gene. We have found that LPS-plus IL-4-induced germ-line transcription of gamma 1 transgenes is likewise inhibited by treatment of B cells with IFN- gamma , so the gamma 1 gene must include the cis-acting element(s) that confers this inhibition. It is also known that CD40 ligation induces a modest amount of germ-line transcripts from the endogenous gamma 1 gene and synergizes with IL-4 to induce large amounts of germ-line transcripts. The gamma 1 transgenes are likewise induced by CD40 ligation, suggesting that the response element(s) for CD40 ligation can be found in the gamma 1 gene. The promoter region for the germ-line transcripts and the I exon are likely to include some of these cis-acting elements. A series of transgenic mice with the promoter/I gamma 1 region conferred low level, lymphoid-specific, RNA expression to a reporter gene, including significant expression in thymocytes. However, the promoter/I gamma 1 transgenes were not regulated like the endogenous gamma 1 gene, in that transcription in splenic B cells was not increased by LPS plus IL-4.