Models for antigen receptor gene rearrangement. II. Multiple rearrangementin the TCR: Allelic exclusion or inclusion?

This series of papers addresses the effects of continuous Ag receptor gene rearrangement in lymphocytes on allelic exclusion. The previous paper discu ssed light chain gene rearrangement and receptor editing in B cells, and sh owed that these processes are ordered on three different levels. This order , combined with the constraints imposed by a strong negative selection, was shown to lead to effective allelic exclusion, In the present paper, we dis cuss rearrangement of TCR genes. In the TCR alpha-chain, allelic inclusion may be the rule rather than the exception, Several previous models, which a ttempted to explain experimental observations, such as the fractions of cel ls containing two productive TCR alpha rearrangements, did not sufficiently account for TCR gene organization, which limits secondary rearrangement, a nd for the effects of subsequent thymic selection. We present here a detail ed, comprehensive computer simulation of TCR gene rearrangement, incorporat ing the interaction of this process with other aspects of lymphocyte develo pment, including cell division, selection, cell death, and maturation. Our model shows how the observed fraction of T cells containing productive TCR alpha rearrangements on both alleles can be explained by the parameters of thymic selection imposed over a random rearrangement process.