Immunoglobulin class-switch DNA recombination: induction, targeting and beyond

Key Points T cell-dependent and T cell-independent primary class-switch DNA recombination (CSR)-inducing stimuli induce activation-induced cytidine deaminase (AID) in a B cell differentiation stage-specific manner. AID expression is further enhanced by secondary CSR-inducing stimuli — namely, interleukin-4, transforming growth factor-β and interferon-γ — through interplay between transcription factors. Targeting of the CSR machinery is made possible by the specific richness of 5′-AGCT-3′ repeats in all S regions and the high avidity of 14-3-3 adaptors for such repeats. Targeting is orchestrated by germline I H -S-C H transcription and epigenetic changes in the S regions that are to undergo recombination; these processes are induced by primary and secondary CSR-inducing stimuli. Histone modifications and factors involved in germline I H -S-C H transcription have an important and active role in the recruitment of 14-3-3 adaptors and AID to S region DNA and in the stabilization of these CSR factors. Proper adaptors (such as 14-3-3 proteins and replication protein A), which do not possess enzymatic activity, function as scaffold proteins for other CSR factors. In addition, enzymes (such as REV1) can function as scaffold elements in CSR. Scaffold proteins that can directly interact with modified histones transduce crucial epigenetic information to AID and other enzymatic effectors of CSR. Here, Paolo Casali and colleagues provide a comprehensive overview of the molecular mechanisms that drive immunoglobulin class-switch DNA recombination (CSR). They describe the signalling determinants of CSR specificity and the epigenetic modifications, transcriptional regulators and scaffold elements that direct the CSR machinery. Class-switch DNA recombination (CSR) of the immunoglobulin heavy chain ( IGH ) locus is central to the maturation of the antibody response and crucially requires the cytidine deaminase AID. CSR involves changes in the chromatin state and the transcriptional activation of the IGH locus at the upstream and downstream switch (S) regions that are to undergo S–S DNA recombination. In addition, CSR involves the induction of AID expression and the targeting of CSR factors to S regions by 14-3-3 adaptors, and it is facilitated by the transcription machinery and by histone modifications. In this Review, we focus on recent advances regarding the induction and targeting of CSR and outline an integrated model of the assembly of macromolecular complexes that tra