Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development

Developing B cells must pass a series of checkpoints that are regulated by membrane-bound Ig mu through the Ig alpha -Ig beta signal transducers. To determine how Ig mu expression affects B cell development and Ab selection in humans we analyzed Ig gene rearrangements in pro-B cells from two patients who are unable to produce Ig mu proteins. We find that Ig mu expression does not affect V-H, D, or J(H) segment usage and is not required for human Ig kappa and Ig lambda recombination or expression. However, the heavy and light chains found in pro-B cells differed from those in peripheral B cells in that they showed unusually long CDR3s. In addition, the Ig kappa repertoire in Ig mu -deficient pro-B cells was skewed to downstream J kappas and upstream V kappas, consistent with persistent secondary V(D)J rearrangements. Thus, Ig mu expression is not required for secondary V(D)J recombination in pro-B cells. However, B cell receptor expression shapes the Ab repertoire in humans and is essential for selection against Ab's with long CDR3s.