The role of germline promoters and I exons in cytokine-induced gene-specific class switch recombination1

Germline transcription precedes class switch recombination. The promoter regions and I exons of these germline transcripts include binding site for activation- and cytokine-induced transcription factors, and the promoter regions/I exons are essential for class switch recombination. Therefore, it is a strong hypothesis that the promoter/I exons regions are responsible for much of cytokine-regulated, gene-specific class switch recombination. We tested this hypothesis by swapping the germline promoter and I exons for the murine γ1 and γ2a H chain genes in a transgene of the entire H chain C region locus. We found that the promoter/I exon for γ1 germline transcripts can direct robust IL-4-induced recombination to the γ2a gene. On the other hand, the promoter/I exon for the γ2a germline transcripts works poorly in the context of the γ1 H chain gene, resulting in expression of γ1 H chains that is less than 1% the wild type level. Nevertheless, the small amount of recombination to the chimeric γ1 gene is induced by IFN-γ. These results suggest that cytokine regulation of CSR, but not the magnitude of CSR, is regulated by the promoter/I exons.