Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell

Significance Antibodies produced by B cells provide a protective barrier to our organism against the penetration and dissemination of microorganisms. Each antibody recognizes a specific antigen through variable (V) region domains of pairs of immunoglobulin (Ig) heavy (H) and light (L) chains. In mammals, VDJ recombination generates a highly diversified preimmune pool of V H and V L domains. Acquisition of a functional V H rearrangement is thought to prevent further VDJ recombination at the IgH locus. Instead, mice cloned from a terminally differentiated B cell unravel the ability of VDJ recombination to revise a functionally rearranged V H gene through VH replacement. We show that up to 20% of the antibody V gene repertoire of mature B-lymphocytes can be generated through VH replacement. In mammals, VDJ recombination is responsible for the establishment of a highly diversified preimmune antibody repertoire. Acquisition of a functional Ig heavy (H) chain variable (V) gene rearrangement is thought to prevent further recombination at the IgH locus. Here, we describe V HQ52 ᴺᵀ; Vκgr32 ᴺᵀ Ig monoclonal mice reprogrammed from the nucleus of an intestinal IgA ⁺ plasma cell. In V HQ52 ᴺᵀ mice, IgA replaced IgM to drive early B-cell development and peripheral B-cell maturation. In V HQ52 ᴺᵀ animals, over 20% of mature B cells disrupted the single productive, nonautoimmune IgH rearrangement through VH replacement and exchanged it with a highly diversified pool of IgH specificities. VH replacement occurred in early pro-B cells, was independent of pre–B-cell receptor signaling, and involved predominantly one adjacent V H germ-line gene. VH replacement was also identified in 5% of peripheral B cells of mice inheriting a different productive V H rearrangement expressed in the form of an IgM H chain. In summary, editing of a productive IgH rearrangement through VH replacement can account for up to 20% of the IgH repertoire expressed by mature B cells.