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

Signaling via the T cell receptor (TCR) is critical during the development, maintenance, and activation of T cells. Quantitative aspects of TCR signaling have an important role during positive and negative selection, lineage choice, and ability to respond to small amounts of antigen. By using a mutant mouse line expressing a hypomorphic allele of the CD3. chain, we show here that the strength of pre-TCR-mediated signaling during T cell development determines the diversity of the TCR beta repertoire available for positive and negative selection, and hence of the final alpha beta TCR repertoire. This finding uncovers an unexpected, pre-TCR signaling-dependent and repertoire-shaping role for beta-selection beyond selection of in-frame rearranged TCR beta chains. Our data furthermore support a model of pre-TCR signaling in which the arrangement of this receptor in stable nanoclusters determines its quantitative signaling capacity.