The E protein-TCF1 axis controls γδ T cell development and effector fate

Shawn P. Fahl; Alejandra V. Contreras; Anjali Verma; Xiang Qiu; Christelle Harly; Freddy Radtke; Juan Carlos Zúñiga-Pflücker; Cornelis Murre; Hai Hui Xue; Jyoti Misra Sen; David L. Wiest

doi:10.1016/j.celrep.2021.108716

The E protein-TCF1 axis controls γδ T cell development and effector fate

Shawn P. Fahl, Alejandra V. Contreras, Anjali Verma, Xiang Qiu, Christelle Harly, Freddy Radtke, Juan Carlos Zúñiga-Pflücker, Cornelis Murre, Hai Hui Xue, Jyoti Misra Sen, David L. Wiest

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

16 Scopus citations

Abstract

TCF1 plays a critical role in T lineage commitment and the development of αβ lineage T cells, but its role in γδ T cell development remains poorly understood. Here, we reveal a regulatory axis where T cell receptor (TCR) signaling controls TCF1 expression through an E-protein-bound regulatory element in the Tcf7 locus, and this axis regulates both γδ T lineage commitment and effector fate. Indeed, the level of TCF1 expression plays an important role in setting the threshold for γδ T lineage commitment and modulates the ability of TCR signaling to influence effector fate adoption by γδ T lineage progenitors. This finding provides mechanistic insight into how TCR-mediated repression of E proteins promotes the development of γδ T cells and their adoption of the interleukin (IL)-17-producing effector fate. IL-17-producing γδ T cells have been implicated in cancer progression and in the pathogenesis of psoriasis and multiple sclerosis.

Original language	English
Article number	108716
Pages (from-to)	108716
Journal	Cell Reports
Volume	34
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2021.108716
State	Published - Feb 2 2021

Keywords

Animals
Cell Differentiation
Hepatocyte Nuclear Factor 1-alpha/metabolism
Humans
Mice
Models, Immunological
Receptors, Antigen, T-Cell, gamma-delta/metabolism
Signal Transduction

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10.1016/j.celrep.2021.108716

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title = "The E protein-TCF1 axis controls γδ T cell development and effector fate",

abstract = "TCF1 plays a critical role in T lineage commitment and the development of αβ lineage T cells, but its role in γδ T cell development remains poorly understood. Here, we reveal a regulatory axis where T cell receptor (TCR) signaling controls TCF1 expression through an E-protein-bound regulatory element in the Tcf7 locus, and this axis regulates both γδ T lineage commitment and effector fate. Indeed, the level of TCF1 expression plays an important role in setting the threshold for γδ T lineage commitment and modulates the ability of TCR signaling to influence effector fate adoption by γδ T lineage progenitors. This finding provides mechanistic insight into how TCR-mediated repression of E proteins promotes the development of γδ T cells and their adoption of the interleukin (IL)-17-producing effector fate. IL-17-producing γδ T cells have been implicated in cancer progression and in the pathogenesis of psoriasis and multiple sclerosis.",

keywords = "Animals, Cell Differentiation, Hepatocyte Nuclear Factor 1-alpha/metabolism, Humans, Mice, Models, Immunological, Receptors, Antigen, T-Cell, gamma-delta/metabolism, Signal Transduction",

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doi = "10.1016/j.celrep.2021.108716",

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AU - Fahl, Shawn P.

AU - Contreras, Alejandra V.

AU - Verma, Anjali

AU - Qiu, Xiang

AU - Harly, Christelle

AU - Radtke, Freddy

AU - Zúñiga-Pflücker, Juan Carlos

AU - Murre, Cornelis

AU - Xue, Hai Hui

AU - Sen, Jyoti Misra

AU - Wiest, David L.

PY - 2021/2/2

Y1 - 2021/2/2

N2 - TCF1 plays a critical role in T lineage commitment and the development of αβ lineage T cells, but its role in γδ T cell development remains poorly understood. Here, we reveal a regulatory axis where T cell receptor (TCR) signaling controls TCF1 expression through an E-protein-bound regulatory element in the Tcf7 locus, and this axis regulates both γδ T lineage commitment and effector fate. Indeed, the level of TCF1 expression plays an important role in setting the threshold for γδ T lineage commitment and modulates the ability of TCR signaling to influence effector fate adoption by γδ T lineage progenitors. This finding provides mechanistic insight into how TCR-mediated repression of E proteins promotes the development of γδ T cells and their adoption of the interleukin (IL)-17-producing effector fate. IL-17-producing γδ T cells have been implicated in cancer progression and in the pathogenesis of psoriasis and multiple sclerosis.

AB - TCF1 plays a critical role in T lineage commitment and the development of αβ lineage T cells, but its role in γδ T cell development remains poorly understood. Here, we reveal a regulatory axis where T cell receptor (TCR) signaling controls TCF1 expression through an E-protein-bound regulatory element in the Tcf7 locus, and this axis regulates both γδ T lineage commitment and effector fate. Indeed, the level of TCF1 expression plays an important role in setting the threshold for γδ T lineage commitment and modulates the ability of TCR signaling to influence effector fate adoption by γδ T lineage progenitors. This finding provides mechanistic insight into how TCR-mediated repression of E proteins promotes the development of γδ T cells and their adoption of the interleukin (IL)-17-producing effector fate. IL-17-producing γδ T cells have been implicated in cancer progression and in the pathogenesis of psoriasis and multiple sclerosis.

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KW - Hepatocyte Nuclear Factor 1-alpha/metabolism

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KW - Models, Immunological

KW - Receptors, Antigen, T-Cell, gamma-delta/metabolism

KW - Signal Transduction

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JO - Cell Reports

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ER -

The E protein-TCF1 axis controls γδ T cell development and effector fate

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The E protein-TCF1 axis controls γδ T cell development and effector fate

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