Models for Antigen Receptor Gene Rearrangement. I. Biased Receptor Editing in B Cells: Implications for Allelic Exclusion

Abstract

Abstract Recent evidence suggests that lymphocyte Ag receptor gene rearrangement does not always stop after the expression of the first productively rearranged receptor. Light chain gene rearrangement in B cells, and α-chain rearrangement in T cells can continue, which raises the question: how is allelic exclusion maintained, if at all, in the face of continued rearrangement? In this and the accompanying paper, we present comprehensive models of Ag receptor gene rearrangement and the interaction of this process with clonal selection. Our B cell model enables us to reconcile observations on the κ:λ ratio and on κ allele usage, showing that B cell receptor gene rearrangement must be a highly ordered, rather than a random, process. We show that order is exhibited on three levels: a preference for rearranging κ rather than λ light chain genes; a preference to make secondary rearrangements on the allele that has already been rearranged, rather than choosing the location of the next rearrangement at random; and a sequentiality of J segment choice within each κ allele. This order, combined with the stringency of negative selection, is shown to lead to effective allelic exclusion.