Pre-existing chromatin accessibility and gene expression differences among naïve CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probed 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 epigenetic differences. Using single-cell RNA sequencing, we showed that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a read-out 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 cell (TFH) 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.