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, ∼28% of naive cells exhibited a preferred lineage choice toward either Th1 or TFH cells. Mechanistically, we found that TCR structure, in particular the CDR3 motif of the TCR α chain, skewed lineage decisions toward the TFH cell fate.
Single-cell lineage mapping of a diverse virus-specific naive CD4 T cell repertoire
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Achia Khatun, Moujtaba Y. Kasmani, Ryan Zander, David M. Schauder, Jeremy P. Snook, Jian Shen, Xiaopeng Wu, Robert Burns, Yi-Guang Chen, Chien-Wei Lin, Matthew A. Williams, Weiguo Cui; Single-cell lineage mapping of a diverse virus-specific naive CD4 T cell repertoire. J Exp Med 1 March 2021; 218 (3): e20200650. doi: https://doi.org/10.1084/jem.20200650
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