Abstract
Immunoglobulin class switch recombination (CSR) plays a crucial role in adaptive immune responses through a change of the effector functions of antibodies and is triggered by T-cell-dependent as well as T-cell-independent antigens. Signals generated following encounter with each type of antigen direct CSR to different isotypes. At the genomic level, CSR occurs between highly repetitive switch sequences located upstream of the constant gene exons of the immunoglobulin heavy chain locus. Transcription of switch sequences is mandatory for CSR and is induced in a stimulation-dependent manner. Switch transcription takes place within dynamic chromatin domains and is regulated by long-range regulatory elements which promote alignment of partner switch regions in CSR centers. Here, we review recent work and models that account for the function of long-range transcriptional regulatory elements and the chromatin-based mechanisms involved in the control of CSR.
Highlights
Institut de Pharmacologie et de Biologie Structurale, IPBS, Universitede Toulouse, CNRS, Universite Paul Sabatier, Toulouse, France
Mature B cells can further diversify the variable regions of Ig heavy chain (IgH) and Ig light chain (IgL) genes through somatic hypermutation (SHM) and the constant (CH) genes of the IgH locus through class switch recombination (CSR)
The critical transcriptional elements involved in Switch transcription (ST) and CSR have long been thought to be confined within the CH region, bordered by the Eμ enhancer and the 3' CTCF binding elements (3'CBEs) (Figure 1)
Summary
B lymphocytes have a remarkable ability to somatically alter their immunoglobulin (Ig) loci at different stages of their development. The enzyme activation-induced cytidine deaminase (AID) is absolutely required for SHM and CSR and initiates these processes via transcription-dependent cytosine deamination of single-stranded DNA targets [5,6,7,8,9]. Mouse B cells are typically induced to switch to IgG3 and IgG2b when activated with lipopolysaccharide (LPS) and to IgG1 and IgE in the presence of LPS+IL4 or anti-CD40+IL4. These culture systems allow the investigators to address B-cell-autonomous mechanisms that are more difficult to tackle in the context of the complex molecular processes and cellular interactions triggered in vivo by antigens [6].
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