Bovolenta, Elena R.García-Cuesta, Eva M.Horndler, LydiaPonomarenko, JuliaSchamel, Wolfgang W.Mellado, MarioCastro, MarioAbia, Davidvan Santen, Hisse M.2022-11-082022-11-082022Bovolenta ER, García-Cuesta EM, Horndler L, Ponomarenko J, Schamel WW, Mellado M, Castro M, Abia D, van Santen HM. A set point in the selection of the αβTCR T cell repertoire imposed by pre-TCR signaling strength. Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2201907119. DOI: 10.1073/pnas.22019071190027-8424http://hdl.handle.net/10230/54743Signaling 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 CD3ζ chain, we show here that the strength of pre-TCR–mediated signaling during T cell development determines the diversity of the TCRβ repertoire available for positive and negative selection, and hence of the final αβTCR repertoire. This finding uncovers an unexpected, pre-TCR signaling–dependent and repertoire–shaping role for β-selection beyond selection of in-frame rearranged TCRβ 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.application/pdfeng© 2022 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1073/pnas.2201907119Diversitypre-TCRRepertoireSignalingβ-selectioninfo:eu-repo/semantics/openAccess