Single-cell lineage mapping of a diverse virus-specific naive CD4 T cell repertoire

Author:

Khatun Achia12ORCID,Kasmani Moujtaba Y.12ORCID,Zander Ryan2ORCID,Schauder David M.12ORCID,Snook Jeremy P.3ORCID,Shen Jian12ORCID,Wu Xiaopeng2ORCID,Burns Robert2ORCID,Chen Yi-Guang145ORCID,Lin Chien-Wei6ORCID,Williams Matthew A.3ORCID,Cui Weiguo12ORCID

Affiliation:

1. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI

2. Blood Research Institute, Versiti Wisconsin, Milwaukee, WI

3. Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT

4. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI

5. Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, WI

6. Institute for Health and Equity, Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI

Abstract

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.

Funder

National Institutes of Health

American Cancer Society

Advancing a Healthier Wisconsin

Cancer Research Institute

National Institute of General Medical Sciences

Medical College of Wisconsin

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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