A set point in the selection of the αβTCR T cell repertoire imposed by pre-TCR signaling strength

Abstract

SignificanceThe ability of the T cell receptor (TCR) to convey signals of different intensity is essential for the generation of a diverse, protecting, and self-tolerant T cell repertoire. We provide evidence that pre-TCR signaling during the first stage of T cell differentiation, thought to only check for in-frame rearrangement of TCRβ gene segments, determines the degree of diversity in a signaling intensity–dependent manner and controls the diversity of the TCR repertoire available for subsequent thymic positive and negative selection. Pre-TCR signaling intensity is regulated by the transmembrane region of its associated CD3ζ chains, possibly by organizing pre-TCRs into nanoclusters. Our data provide insights into immune receptor signaling mechanisms and reveal an additional checkpoint of T cell repertoire diversity.