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

• DOI: 10.1073/pnas.2201907119
• Publication Date: 2022-05-26T18:04:11Z
• Authors: Elena R. Bovolenta; Eva M. García-Cuesta; Lydia Horndler; Julia Ponomarenko; Wolfgang W. Schamel; Mario Mellado; Mario Castro; David Abia; Hisse M. van Santen
• Keywords: 0301 basic medicine; Diversity; 0303 health sciences; CD3 Complex; Receptors, Antigen, T-Cell, alpha-beta; T-Lymphocytes; repertoire; pre-TCR; Cell Differentiation; diversity; pre-TCR; repertoire; signaling; β-selection; Biological Sciences; Signaling; Mice, Mutant Strains; diversity; Mice; 03 medical and health sciences; Animals; Repertoire; signaling; β-selection; Signal Transduction

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.