We observed no significant difference in the number of B cells expressing the IgMa and IgMb alleles, nor in the number of κ+ and λ+ B cells, between 56Rki and DTG mice (see Supplementary material, Fig. S4b and Table S2). B cells undergo Selleckchem CHIR 99021 a series of RAG-mediated V(D)J rearrangement events and selection processes during their development to obtain a combination of functionally rearranged immunoglobulin heavy and light chain genes that encode a BCR with an antigenic

specificity that is either non-autoreactive or possesses a level of self-reactivity that is tolerated by the host.40 Primary V(D)J rearrangements occur during the pro-B-cell and pre-B-cell stages to generate an initial antigen receptor specificity that is subsequently tested for self-reactivity. Should the primary rearrangements yield an antigenic specificity that is not

tolerated by the host, the cell may be rendered anergic or undergo developmental arrest to initiate secondary V(D)J rearrangements (generally involving the light chain loci) to edit receptor specificity far enough away from self-reactivity to become innocuous to the host. Should these attempts fail to achieve a tolerated specificity, the cell will typically be deleted from the repertoire. The anatomical sites and developmental stages

that support secondary V(D)J rearrangement to edit self-reactivity may be diverse, depending selleck chemicals clonidine on the antigenic specificity of the heavy chain and light chain (with a strongly self-reactive heavy chain possibly eliciting editing earlier in B-cell development than self-specificity imparted by both heavy and light chains),41 whether editing involves transgene-encoded immunoglobulin genes (which may be subject to antigen-independent as well as antigen-dependent editing),39 and where the antigen is encountered (centrally, as self-antigen, or peripherally, to suppress autoreactivity generated during an immune response 42). In principle, expressing catalytically inactive RAG1 in an otherwise RAG-competent host may impair either primary or secondary V(D)J rearrangement events. Which events are impaired would depend on whether inactive RAG1 is expressed in sufficient excess over the endogenous protein to function as a dominant negative at the developmental stages that support primary or secondary V(D)J rearrangements. The dnRAG1 mice described in this study do not exhibit an obvious impairment in primary V(D)J recombination, as evidenced by a normal abundance and distribution of thymocyte populations and bone marrow pre-B-cell and pro-B-cell subsets (Fig. 2a, see Supplementary material, Fig.