RSSs set the odds for exclusion

Abstract

In this issue of JEM, Wu et al. (https://doi.org/10.1084/jem.20200412) provide new insights into allelic exclusion. They demonstrate that Vβ-to-DβJβ rearrangement occurs stochastically on two competing Tcrb alleles, with suboptimal Vβ recombination signal sequences limiting synchronous rearrangements and essential for allelic exclusion.

Insights from Michael S. Krangel.

RSS replacement increases the probability of synchronous V_β-to-D_βJ_β rearrangement and disrupts allelic exclusion. This image shows the Tcrb locus, depicting subsets of V_β and Trbj1 gene segments; for simplicity, the Trbd2-Trbj2-Trbc2 cluster (downstream of Trbd1-Trbj1-Trbc1) is not shown. Small triangles indicate 12-bp spacer RSSs; larger triangles indicate 23-bp spacer RSSs; red indicates optimal RSSs; and blue indicates suboptimal RSSs. Tcrb locus D_β-to-J_β rearrangement occurs first and is biallelic, whereas V_β-to-D_βJ_β rearrangement occurs subsequently, and in wild-type, occurs one allele at a time (top). Replacing the suboptimal Trbv2 RSS with the highly efficient Trbd1 3′ RSS increases the frequency of Trbv2 rearrangement and increases the odds that Trbv2 will rearrange in synchrony with a V_β gene segment on the opposing allele (bottom). Synchronous allelic rearrangement cannot be suppressed by feedback inhibition and results in allelic inclusion.