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) cell versus non-T 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.