Regulation of TCRβ Allelic Exclusion by Gene Segment Proximity and Accessibility

Abstract

Ag receptor loci are regulated to promote allelic exclusion, but the mechanisms are not well understood. Assembly of a functional TCR β-chain gene triggers feedback inhibition of Vβ-to-DJβ recombination in double-positive (DP) thymocytes, which correlates with reduced Vβ chromatin accessibility and a locus conformational change that separates Vβ from DJβ gene segments. We previously generated a Tcrb allele that maintained Vβ accessibility but was still subject to feedback inhibition in DP thymocytes. We have now further analyzed the contributions of chromatin accessibility and locus conformation to feedback inhibition using two novel TCR alleles. We show that reduced Vβ accessibility and increased distance between Vβ and DJβ gene segments both enforce feedback inhibition in DP thymocytes.