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 VH11Vkappa9 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, VH11Vkappa9 and VH12Vkappa4. We have found that the development of B-lineage cells with a VH11 rearrangement is surprisingly restricted at several crucial bottlenecks: (i). one of the most common VH11 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 VH11- micro chains lacking N-addition are favored for progression to the B-cell stage, eliminating most bone marrow VH11 rearrangements; and (iii). only a subset of Vkappa-light chains combine with VH11 heavy chain to foster progression to the mature B-cell stage. Together, these constrain VH11 generation to fetal development and may favor production of B cells with the prototype VH11Vkappa9 BCR.