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

Bovolenta, Elena R.; García-Cuesta, Eva M.; Horndler, Lydia; Ponomarenko, Julia; Schamel, Wolfgang W.; Mellado, Mario; Castro, Mario; Abia, David; van Santen, Hisse M.

doi:http://dx.doi.org/10.1073/pnas.2201907119

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

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Bovolenta 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.2201907119

Abstract

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 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.