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

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.