Single-Cell Lineage Mapping Of A Diverse Virus-Specific Naive Cd4 T Cell Repertoire

Tracking how individual naive T cells from a natural TCR repertoire clonally expand, differentiate, and make lineage choices in response to an infection has not previously been possible. Here, using single-cell sequencing technology to identify clones by their unique TCR sequences, we were able to trace the clonal expansion, differentiation trajectory, and lineage commitment of individual virus-specific CD4 T cells during an acute lymphocytic choriomeningitis virus (LCMV) infection. Notably, we found previously unappreciated clonal diversity and cellular heterogeneity among virus-specific helper T cells. Interestingly, although most naive CD4 T cells gave rise to multiple lineages at the clonal level, similar to 28% of naive cells exhibited a preferred lineage choice toward either Th1 or T-FH cells. Mechanistically, we found that TCR structure, in particular the CDR3 motif of the TCR alpha chain, skewed lineage decisions toward the T-FH cell fate.