Switch Region Identity Plays an Important Role in Ig Class Switch Recombination

Ig class switch recombination (CSR) is regulated through long-range intrachromosomal interactions between germline transcript promoters and enhancers to initiate transcription and create chromatin accessible to activation-induced deaminase attack. CSR occurs between switch (S) regions that flank C mu and downstream C-H regions and functions via an intrachromosomal deletional event between the donor S mu region and a downstream S region. It is unclear to what extent S region primary sequence influences differential targeting of CSR to specific isotypes. We address this issue in this study by generating mutant mice in which the endogenous S gamma 3 region was replaced with size-matched S gamma 1 sequence. B cell activation conditions are established that support robust gamma 3 and gamma 1 germline transcript expression and stimulate IgG1 switching but suppress IgG3 CSR. We found that the S gamma 1 replacement allele engages in mu ->gamma 3 CSR, whereas the intact allele is repressed. We conclude that S region identity makes a significant contribution to CSR. We propose that the S gamma 1 region is selectively targeted for CSR following the induction of an isotype-specific factor that targets the S region and recruits CSR machinery. The Journal of Immunology, 2010, 184: 6242-6248.