The roles of recombination signal sequence efficiency and location within the TCR β locus on the relative frequencies with which V β gene segments participate in V(D)J recombination

Abstract

The different T cell receptor (TCR) β variable (Vβ) gene segments do not appear in the naïve TCR repertoire with equal frequencies. To identify the relative roles of recombination signal (RS) sequence efficiency and location within the TCRβ locus in determining the bias in Vβ gene segment utilization, we are studying TCR diversification after thymus transplantation in athymic infants with complete DiGeorge anomaly. Thymus transplantation reconstitutes T cells, and the course of T cell development allows study of TCR diversification. We sequenced mRNA from peripheral blood T cells sampled from two patients at multiple times after thymus transplantation. For each of six Vβ gene segments, we estimated the diversity of rearrangements from the number of unique rearrangements utilizing that gene segment and the number of identical sequences for each unique rearrangement. The RS recombination efficiency was predicted using the RS Information Content (RIC) score computed using a statistical model of mouse RS. We find that Vβ gene segment diversity varies significantly in the early repertoire indicating differences in the relative frequencies of recombination. Neither RS efficiency nor distance from the D‐J cluster solely determine the observed differences, rather the two factors appear to interact, jointly influencing recombination frequencies.This work is supported by an NIH grant to MLM and a BWF award to LGC.