Strong TCR signaling prolongs lineage uncertainty during MHC-I specific positive selection (HEM8P.241)

Abstract

Abstract CD4/CD8 lineage choice in the thymus is primarily determined by the duration of TCR signaling during positive selection. Positive selection signaling by MHC-I ligands is of relatively short duration because CD8 coreceptor expression is terminated. However, the duration of TCR signaling during MHC-I specific positive selection should, in theory, also be affected by TCR affinity as well as coreceptor signal strength, but how TCR affinity and coreceptor signal strength affect MHC-I specific positive selection is not really known. To address this point, we used RAG-deficient mice expressing a panel of MHC-I restricted TCR transgenes with TCRs of different affinities for in vivo self ligands, and used genetically engineered mouse models that modulate the intensity of TCR signaling. Our data reveal that TCR signal intensity dictates how long MHC-I signaled thymocytes remain lineage-uncommitted before they express Runx3 and undergo CD8 lineage commitment. Furthermore, our data reveal that lineage errors by very high affinity TCR undergoing MHC-I specific positive selection do not normally occur because CD8 coreceptors have evolved to provide only weak Lck/coreceptor signals. We conclude that TCR signal intensity dramatically affects the timing of lineage fate during MHC-I specific positive selection and that error-free CD8 lineage choice is dependent on weak signaling by the CD8 coreceptor.