NEWS AND VIEWS Recombination of variable, diversity and joining regions (V(D)J recombination) affords the immune system the ability to encode an enormous repertoire of antigen receptors with a relatively modest invest- ment of genetic capacity. This reliance on combinatorial diversity introduces prob- lems, however. Developing lymphocytes must have a way to monitor the assembly process to prevent expression of multiple functional receptors in a given cell (allelic exclusion) and to exercise ‘quality control’ on the proteins produced. Progenitor B cells do so through assembly in the membrane of a ‘pre-B cell receptor’ (pre-BCR), which is essential for normal development. Whereas the mature BCR initiates signaling through interaction with its cognate antigen, it remains uncertain how the pre-BCR signals. In this issue of Nature Immunology, one of the discoverers of the pre-BCR and his col- league present unexpected data showing that conserved pre-BCR components may inter- act with one another to induce receptor aggregation and signaling without involve- ment of an exogenous ligand 1 . Rearrangement of the immunoglobulin heavy-chain (H) gene (Igh) precedes Igk or Igl light-chain gene rearrangement, with D H -to-J H rearrangement occurring before V H -to-DJ H rearrangement. Because of the imprecise nature of the joining step and the addition of N regions to Igh coding joints, two of three times V(D)J recombination generates out-of-frame (nonproductive) alleles. In addition, the requirement for two Mark Schlissel is in the Department of Molecular and Cell Biology, University of California, Berkeley, 439 LSA, Berkeley, California 94720-3200, USA. e-mail: mss@uclink4.berkeley.edu How pre-B cells know when they have it right Mark Schlissel Early B cell development faces a critical checkpoint at the pro-B → pre-B transition stage, at which proper assembly and surface expression of an immunoglobulin heavy chain is somehow signaled by the pre-B cell receptor. Triggering of this signal might not require exogenous ligands. NATURE IMMUNOLOGY VOLUME 4 NUMBER 9 SEPTEMBER 2003 817 Figure 1 The pre-BCR: signals and possible signaling mechanisms. (a) The progression of developing B cells across the pro-B-to-pre-B cell transition. Pro-B cells rearrange gene segments in an attempt to generate an immunoglobulin heavy-chain gene encoding a protein capable of pairing with SLCs to form a pre-BCR. Early pre-B cells undergo multiple rounds of cell division, inactivate further heavy-chain gene rearrangement (–) and activate light chain gene rearrangement (+). (b) Models proposed to explain the initiation of the pre-BCR signal upon surface expression of the pre-BCR. Inset, the surrogate light chains consist of Ig-like (orange and purple boxes) and non-Ig like (red and green boxes) domains, which presumably assemble with a heavy chain into an Ig-like structure with a new central region. V V-to-J V κ V- V-to-J V κ κ V V-to-J V κ V V-to-J V κ V-to-(D)J o-(D)J o )J J V( V(D)J (D + Pro-B Pro B Early pre-B – + — — — — Ig-like N C Ig-like N C V preB λ5 Proliferation P if Transcriptiona al T regulation r Late pre-B No ligand Stromal cell ligand "Self" ligand — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — C.C rearrangements to generate a complete heavy-chain variable region exon results in considerable length heterogeneity that is not found in light-chain gene rearrangements (because only a single recombination event is required and because N regions are rare in © 2003 Nature Publishing Group http://www.nature.com/natureimmunology