Selection during development of VH11+B cells:: a model for natural autoantibody-producing CD5+ B cells

Natural autoantibodies constitute a large portion of serum immunoglobulin M (IgM) and bridge the adaptive and innate immune systems, serving as a rapid response to common pathogens. Many arise from a distinctive subset of B cells, termed B-1, that express CD5. Here, we describe our studies with a representative CD5(+) B-cell-derived natural autoantibody, the V(H)11V(kappa)9 B-cell receptor (BCR) that binds a determinant on senescent erythrocytes. This specificity represents 5-10% of the CD5(+) B-cell subset, with a large portion accounted for by two novel BCRs, V(H)11V(kappa)9 and V(H)12V(kappa)4. We have found that the development of B-lineage cells with a V(H)11 rearrangement is surprisingly restricted at several crucial bottlenecks: (i) one of the most common V(H)11 rearrangements generates a heavy-chain protein that only inefficiently assembles a pre-BCR, key for recombinase-activating gene downregulation/allelic exclusion and pre-B-clonal expansion; (ii) cells containing V(H)11-mu chains lacking N-addition a-re favored for progression to the B-cell stage, eliminating most bone marrow V(H)11 rearrangements; and (iii) only a subset of V.-light chains combine with V(H)11 heavy chain to foster progression to the mature B-cell stage. Together, these constrain V(H)11 generation to fetal development and may favor production of B cells with the prototype V(H)11V(kappa)9 BCR.