Models for antigen receptor gene rearrangement. I. Biased receptor editingin B cells: Implications for allelic exclusion

Recent evidence suggests that lymphocyte Ag receptor gene rearrangement doe s not always stop after the expression of the first productively rearranged receptor, Light chain gene rearrangement in B cells, and alpha-chain rearr angement in T cells can continue, which raises the question: how is allelic exclusion maintained, if at all, in the face of continued rearrangement? I n this and the accompanying paper, we present comprehensive models of Ag re ceptor gene rearrangement and the interaction of this process with clonal s election. Our B cell model enables us to reconcile observations on the kapp a:lambda ratio and on kappa 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 kappa rather than lambda 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 sequential ity of J segment choice within each kappa allele, This order, combined with the stringency of negative selection, is shown to lead to effective alleli c exclusion.