Immunoglobulin heavy-chain switching is effected by a DNA recombination event that replaces the C(μ) gene with one of the other heavy-chain constant-region (C(H)) genes located 3' to the C(μ) gene. How the specificity of this event is controlled is unknown. However, it has been shown that IgM+ cells capable of switching to specific isotypes have the corresponding unrearranged C(H) genes in an accessible or active chromatin state, as demonstrated by the fact that these specific C(H) genes are hypomethylated and are transcriptionally active. We now report that the RNAs transcribed from specific unrearranged C(H) genes are induced prior to switching under conditions that promote switching to these specific C(H) genes. For example, we find that bacterial lipopolysaccharide, which induces the IgM+ cell line I.29μ to switch to IgA, induces transcripts from the germ-line C(α) gene(s) in I.29μ cells prior to switch recombination. Two preparations of T-cell lymphokines (recombinant interleukin 4 and supernatant from the T-cell line 2.19, which contains interleukins 4 and 5) that promote switching to specific isotypes by lipopolysaccharide-treated spleen cells induce transcripts from the corresponding germ-line C(H) genes prior to expression of the new isotypes. For example, interleukin 4, which appears to be necessary for switching to IgE in vitro and in vivo, induces within 2 days large increases in germ-line C(ε) transcripts in lipopolysaccharide-treated spleen cells and in I.29μ cells. The most straightforward interpretation of our data is that these lymphokines direct switching to specific isotypes by activating specific C(H) genes, making them accessible to the putative switch recombinase.
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 1988|
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