A dynamical model of TCRβ gene recombination: Coupling the initiation of Dβ-Jβ rearrangement to TCRβ allelic exclusion

Abstract

AbstractOne paradigm of random monoallelic gene expression is that of T-cell receptor (TCR)β allelic exclusion in T lymphocytes. However, the dynamics that sustain asymmetric choice in TCRβ dual allele usage and the production of TCRβ monoallelic expressing T-cells remain poorly understood. Here, we develop a computational model to explore a scheme of TCRβ allelic exclusion based on the stochastic initiation of DNA rearrangement [V(D)J recombination] at homologous alleles in T-cell progenitors, and thus account for the genotypic profiles typically associated with allelic exclusion in differentiated T-cells. Disturbances in these dynamics at the level of an individual allele have limited consequences on these pro1les, robust feature of the system that is underscored by our simulations. Our study predicts a biological system in which locus-specific, prime epigenetic allelic activation effects set the stage to both optimize the production of TCRβ allelically excluded T-cells and curtail the emergence of their allelically included counterparts.