GAMMA-1 HEAVY-CHAIN TRANSGENES ARE RESPONSIVE TO IFN-GAMMA REPRESSIONAND CD40 LIGATION

The cis-acting elements that regulate production of germ-line transcri pts from Ig heavy chain genes and subsequent switch recombination to t hose 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-li ne transcription like the endogenous gamma 1 gene. Transcripts from su ch 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 no nlymphoid tissues, We have now found that transcripts from these trans genes 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 induc tion 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 tr ansgenes is likewise inhibited by treatment of B cells with IFN-gamma, so the gamma 1 gene must include the cis-acting element(s) that confe rs this inhibition. It is also known that CD40 ligation induces a mode st amount of germ-line transcripts from the endogenous gamma 1 gene an d synergizes with IL-4 to induce large amounts of germ-line transcript s, The gamma 1 transgenes are likewise induced by CD40 ligation, sugge sting that the response element(s) for CD40 ligation can be found in t he 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 conferre d low level, lymphoid-specific, RNA expression to a reporter gene, inc luding significant expression in thymocytes. However, the promoter/I g amma 1 transgenes were not regulated like the endogenous gamma 1 gene, in that transcription in splenic B cells was not increased by LPS plu s IL-4.