Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential
Dakota Rogers, Aditi Sood, HanChen Wang, Jasper J. P. van Beek, Thomas J. Rademaker, Patricio Artusa, C. L. Schneider, Connie Shen, Dylan C. Wong, Aanya Bhagrath, Marie‐Ève Lebel, Stephanie A. Condotta, Martin J. Richer, Andrew J. Martins, John S. Tsang, Luis B. Barreiro, Paul François, David Langlais, Heather J. Melichar, Johannes Textor, Judith N. Mandl
Abstract
CD4 + 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 (T FH ) cell versus non-T FH 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.