Rogers, DakotaSood, AditiWang, HanChenvan Beek, Jasper J.P.Rademaker, Thomas J.Artusa, PatricioSchneider, CaitlinShen, ConnieWong, Dylan C.Bhagrath, AanyaLebel, Marie-ÈveCondotta, Stephanie A.Richer, Martin J.Martins, Andrew J.Tsang, John S.Barreiro, Luis B.François, PaulLanglais, DavidMelichar, Heather J.Textor, JohannesMandl, Judith N.2023-01-302023-01-302021-11Rogers, D., Sood, A., Wang, H., Beek, J. J. P. van, Rademaker, T. J., Artusa, P., Schneider, C., Shen, C., Wong, D. C., Bhagrath, A., Lebel, M.-È., Condotta, S. A., Richer, M. J., Martins, A. J., Tsang, J. S., Barreiro, L. B., François, P., Langlais, D., Melichar, H. J., … Mandl, J. N. (2021). Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential. Cell Reports, 37(9). https://doi.org/10.1016/j.celrep.2021.1100642211-1247https://hdl.handle.net/1805/31037CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential.en-USAttribution-NonCommercial-NoDerivatives 4.0 Internationalcell heterogeneityT cell differentiationtranscriptomeArticle