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

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

doi:10.1084/JEM.20200650

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

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^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

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 T_FH cells. Mechanistically, we found that TCR structure, in particular the CDR3 motif of the TCR α chain, skewed lineage decisions toward the T_FH cell fate.

Original language	English (US)
Article number	e20200650
Journal	Journal of Experimental Medicine
Volume	218
Issue number	3
DOIs	https://doi.org/10.1084/JEM.20200650
State	Published - Mar 1 2021

Funding

This work is supported by National Institutes of Health grants AI125741 (W. Cui), DK127526 (M.Y. Kasmani), AI153537 (R. Zander), DK108557 (D.M. Schauder), DK107541 (Y.-G. Chen), DK121747 (Y.-G. Chen), and AI137248 (M.A. Williams); by an American Cancer Society Research Scholar Grant (W. Cui); and by an Advancing a Healthier Wisconsin Endowment Grant (W. Cui). R. Zander is supported by the Cancer Research Institute Irvington Fellowship. D.M. Schauder and M.Y. Kasmani are members of the Medical Scientist Training Program at the Medical College of Wisconsin, which is partially supported by a training grant from the National Institute of General Medical Sciences (T32-GM080202). This research was completed in part with computational resources and technical support provided by the Research Computing Center at the Medical College of Wisconsin.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1084/JEM.20200650

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title = "Single-cell lineage mapping of a diverse virus-specific naive CD4 T cell repertoire",

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.",

author = "Achia Khatun and Kasmani, {Moujtaba Y.} and Ryan Zander and Schauder, {David M.} and Snook, {Jeremy P.} and Jian Shen and Xiaopeng Wu and Robert Burns and Chen, {Yi Guang} and Lin, {Chien Wei} and Williams, {Matthew A.} and Weiguo Cui",

note = "Funding Information: This work is supported by National Institutes of Health grants AI125741 (W. Cui), DK127526 (M.Y. Kasmani), AI153537 (R. Zander), DK108557 (D.M. Schauder), DK107541 (Y.-G. Chen), DK121747 (Y.-G. Chen), and AI137248 (M.A. Williams); by an American Cancer Society Research Scholar Grant (W. Cui); and by an Advancing a Healthier Wisconsin Endowment Grant (W. Cui). R. Zander is supported by the Cancer Research Institute Irvington Fellowship. D.M. Schauder and M.Y. Kasmani are members of the Medical Scientist Training Program at the Medical College of Wisconsin, which is partially supported by a training grant from the National Institute of General Medical Sciences (T32-GM080202). This research was completed in part with computational resources and technical support provided by the Research Computing Center at the Medical College of Wisconsin. Publisher Copyright: {\textcopyright} 2020 Khatun et al.",

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AU - Kasmani, Moujtaba Y.

AU - Zander, Ryan

AU - Schauder, David M.

AU - Snook, Jeremy P.

AU - Shen, Jian

AU - Wu, Xiaopeng

AU - Burns, Robert

AU - Chen, Yi Guang

AU - Lin, Chien Wei

AU - Williams, Matthew A.

AU - Cui, Weiguo

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PY - 2021/3/1

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N2 - 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.

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

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