Elucidation of the enigmatic IgD class-switch recombination via germline deletion of the IgH 3′ regulatory region

Classical class-switch recombination (cCSR) substitutes the C(μ) gene with C(γ), C(ε), or C(α), thereby generating IgG, IgE, or IgA classes, respectively. This activation-induced deaminase (AID)–driven process is controlled by the IgH 3′ regulatory region (3′RR). Regulation of rare IgD CSR events has been enigmatic. We show that μδCSR occurs in mouse mesenteric lymph node (MLN) B cells and is AID-dependent. AID attacks differ from those in cCSR because they are not accompanied by extensive somatic hypermutation (SHM) of targeted regions and because repaired junctions exhibit features of the alternative end-joining (A-EJ) pathway. In contrast to cCSR and SHM, μδCSR is 3′RR-independent, as its absence affects neither breakpoint locations in S(μ)- and S(δ)-like (σ(δ)) nor mutation patterns at S(μ)-σ(δ) junctions. Although mutations occur in the immediate proximity of the μδ junctions, SHM is absent distal to the junctions within both S(μ) and rearranged VDJ regions. In conclusion, μδCSR is active in MLNs, occurs independently of 3′RR-driven assembly, and is even dramatically increased in 3′RR-deficient mice, further showing that its regulation differs from cCSR.