Single-cell multi-omic analysis of thymocyte development reveals NFAT as a driver of CD4/CD8 lineage commitment

Zoë Steier; Laura L. McIntyre; Lydia K. Lutes; Tse-Shun Huang; Ellen A. Robey; Nir Yosef; Aaron Streets

Single-cell multi-omic analysis of thymocyte development reveals NFAT as a driver of CD4/CD8 lineage commitment

Zoë Steier, Laura L. McIntyre, Lydia K. Lutes, Tse-Shun Huang, Ellen A. Robey, Nir Yosef, Aaron Streets

Research output: Contribution to journal › Article

Abstract

CD4 and CD8 T cells play critical roles in the mammalian immune system. While their development within the thymus from the CD4+CD8+ stage has been widely studied as a model of lineage commitment, the underlying mechanism remains unclear. To deconstruct this process, we apply CITE-seq, measuring the transcriptome and over 100 surface proteins in thymocytes from wild-type and lineage-restricted mice. We jointly analyze the paired measurements to build a comprehensive timeline of RNA and protein expression in each lineage, supporting a sequential model of lineage determination in which both lineages go through an initial phase of CD4 lineage audition, which is followed by divergence and specification of CD8 lineage cells. We identify early differences implicating T cell receptor signaling via calcineurin-NFAT in driving CD4 lineage commitment. Pharmacological inhibition validates the requirement of calcineurin- NFAT for CD4, but not CD8, lineage development, providing insight into the CD4/CD8 commitment mechanism.

Original language	English
Number of pages	54
Journal	bioRxiv
State	In preparation - 13 Jul 2021
Externally published	Yes

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https://doi.org/10.1101/2021.07.12.452119License: CC BY-NC-ND

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@article{c875aba62c7140f7a4763eb5d81d039a,

title = "Single-cell multi-omic analysis of thymocyte development reveals NFAT as a driver of CD4/CD8 lineage commitment",

abstract = "CD4 and CD8 T cells play critical roles in the mammalian immune system. While their development within the thymus from the CD4+CD8+ stage has been widely studied as a model of lineage commitment, the underlying mechanism remains unclear. To deconstruct this process, we apply CITE-seq, measuring the transcriptome and over 100 surface proteins in thymocytes from wild-type and lineage-restricted mice. We jointly analyze the paired measurements to build a comprehensive timeline of RNA and protein expression in each lineage, supporting a sequential model of lineage determination in which both lineages go through an initial phase of CD4 lineage audition, which is followed by divergence and specification of CD8 lineage cells. We identify early differences implicating T cell receptor signaling via calcineurin-NFAT in driving CD4 lineage commitment. Pharmacological inhibition validates the requirement of calcineurin- NFAT for CD4, but not CD8, lineage development, providing insight into the CD4/CD8 commitment mechanism.",

author = "Zo{\"e} Steier and McIntyre, {Laura L.} and Lutes, {Lydia K.} and Tse-Shun Huang and Robey, {Ellen A.} and Nir Yosef and Aaron Streets",

year = "2021",

month = jul,

day = "13",

language = "الإنجليزيّة",

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TY - JOUR

T1 - Single-cell multi-omic analysis of thymocyte development reveals NFAT as a driver of CD4/CD8 lineage commitment

AU - Steier, Zoë

AU - McIntyre, Laura L.

AU - Lutes, Lydia K.

AU - Huang, Tse-Shun

AU - Robey, Ellen A.

AU - Yosef, Nir

AU - Streets, Aaron

PY - 2021/7/13

Y1 - 2021/7/13

N2 - CD4 and CD8 T cells play critical roles in the mammalian immune system. While their development within the thymus from the CD4+CD8+ stage has been widely studied as a model of lineage commitment, the underlying mechanism remains unclear. To deconstruct this process, we apply CITE-seq, measuring the transcriptome and over 100 surface proteins in thymocytes from wild-type and lineage-restricted mice. We jointly analyze the paired measurements to build a comprehensive timeline of RNA and protein expression in each lineage, supporting a sequential model of lineage determination in which both lineages go through an initial phase of CD4 lineage audition, which is followed by divergence and specification of CD8 lineage cells. We identify early differences implicating T cell receptor signaling via calcineurin-NFAT in driving CD4 lineage commitment. Pharmacological inhibition validates the requirement of calcineurin- NFAT for CD4, but not CD8, lineage development, providing insight into the CD4/CD8 commitment mechanism.

AB - CD4 and CD8 T cells play critical roles in the mammalian immune system. While their development within the thymus from the CD4+CD8+ stage has been widely studied as a model of lineage commitment, the underlying mechanism remains unclear. To deconstruct this process, we apply CITE-seq, measuring the transcriptome and over 100 surface proteins in thymocytes from wild-type and lineage-restricted mice. We jointly analyze the paired measurements to build a comprehensive timeline of RNA and protein expression in each lineage, supporting a sequential model of lineage determination in which both lineages go through an initial phase of CD4 lineage audition, which is followed by divergence and specification of CD8 lineage cells. We identify early differences implicating T cell receptor signaling via calcineurin-NFAT in driving CD4 lineage commitment. Pharmacological inhibition validates the requirement of calcineurin- NFAT for CD4, but not CD8, lineage development, providing insight into the CD4/CD8 commitment mechanism.

M3 - مقالة

SN - 2692-8205

JO - bioRxiv

JF - bioRxiv

ER -

Single-cell multi-omic analysis of thymocyte development reveals NFAT as a driver of CD4/CD8 lineage commitment

Abstract

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