Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

Kerstin Wendland; Kristoffer Niss; Knut Kotarsky; Nikita Yeuk Hung Wu; Andrea J. White; Lars Johan Jendholm; Aymeric Rivollier; Jose M.G. Izarzugaza; Søren Brunak; Georg A Holländer; Graham Anderson; Katarzyna M. Sitnik; William W. Agace

doi:10.4049/jimmunol.1800418

Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

Kerstin Wendland, Kristoffer Niss, Knut Kotarsky, Nikita Yeuk Hung Wu, Andrea J. White, Lars Johan Jendholm, Aymeric Rivollier, Jose M.G. Izarzugaza, Søren Brunak, Georg A Holländer, Graham Anderson, Katarzyna M. Sitnik, William W. Agace

Disease Systems Biology Program

9 Citationer (Scopus)

Abstract

Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. In this study, we show a key in vivo role for the vitamin A metabolite, retinoic acid (RA), in TEC homeostasis. In the absence of RA signaling in TEC, cortical TEC (cTEC) and CD80loMHC class IIlo medullary TEC displayed subset-specific alterations in gene expression, which in cTEC included genes involved in epithelial proliferation, development, and differentiation. Mice whose TEC were unable to respond to RA showed increased cTEC proliferation, an accumulation of stem cell Ag-1hi cTEC, and, in early life, a decrease in medullary TEC numbers. These alterations resulted in reduced thymic cellularity in early life, a reduction in CD4 single-positive and CD8 single-positive numbers in both young and adult mice, and enhanced peripheral CD8+ T cell survival upon TCR stimulation. Collectively, our results identify RA as a regulator of TEC homeostasis that is essential for TEC function and normal thymopoiesis.

Originalsprog	Engelsk
Tidsskrift	Journal of Immunology
Vol/bind	201
Udgave nummer	2
Sider (fra-til)	524-532
Antal sider	9
ISSN	0022-1767
DOI	https://doi.org/10.4049/jimmunol.1800418
Status	Udgivet - 15 jul. 2018

Adgang til dokumentet

10.4049/jimmunol.1800418

524.full.pdfForlagets udgivne version, 1,92 MB

https://www.jimmunol.org/content/jimmunol/201/2/524.full.pdf

Citationsformater

@article{510e36440e544b4b8d827f90b79c73e9,

title = "Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis",

abstract = "Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. In this study, we show a key in vivo role for the vitamin A metabolite, retinoic acid (RA), in TEC homeostasis. In the absence of RA signaling in TEC, cortical TEC (cTEC) and CD80loMHC class IIlo medullary TEC displayed subset-specific alterations in gene expression, which in cTEC included genes involved in epithelial proliferation, development, and differentiation. Mice whose TEC were unable to respond to RA showed increased cTEC proliferation, an accumulation of stem cell Ag-1hi cTEC, and, in early life, a decrease in medullary TEC numbers. These alterations resulted in reduced thymic cellularity in early life, a reduction in CD4 single-positive and CD8 single-positive numbers in both young and adult mice, and enhanced peripheral CD8+ T cell survival upon TCR stimulation. Collectively, our results identify RA as a regulator of TEC homeostasis that is essential for TEC function and normal thymopoiesis.",

author = "Kerstin Wendland and Kristoffer Niss and Knut Kotarsky and Wu, {Nikita Yeuk Hung} and White, {Andrea J.} and Jendholm, {Lars Johan} and Aymeric Rivollier and Izarzugaza, {Jose M.G.} and S{\o}ren Brunak and Holl{\"a}nder, {Georg A} and Graham Anderson and Sitnik, {Katarzyna M.} and Agace, {William W.}",

note = "Copyright {\textcopyright} 2018 by The American Association of Immunologists, Inc.",

year = "2018",

month = jul,

day = "15",

doi = "10.4049/jimmunol.1800418",

language = "English",

volume = "201",

pages = "524--532",

journal = "Journal of Immunology",

issn = "0022-1767",

publisher = "American Association of Immunologists",

number = "2",

}

TY - JOUR

T1 - Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

AU - Wendland, Kerstin

AU - Niss, Kristoffer

AU - Kotarsky, Knut

AU - Wu, Nikita Yeuk Hung

AU - White, Andrea J.

AU - Jendholm, Lars Johan

AU - Rivollier, Aymeric

AU - Izarzugaza, Jose M.G.

AU - Brunak, Søren

AU - Holländer, Georg A

AU - Anderson, Graham

AU - Sitnik, Katarzyna M.

AU - Agace, William W.

PY - 2018/7/15

Y1 - 2018/7/15

N2 - Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. In this study, we show a key in vivo role for the vitamin A metabolite, retinoic acid (RA), in TEC homeostasis. In the absence of RA signaling in TEC, cortical TEC (cTEC) and CD80loMHC class IIlo medullary TEC displayed subset-specific alterations in gene expression, which in cTEC included genes involved in epithelial proliferation, development, and differentiation. Mice whose TEC were unable to respond to RA showed increased cTEC proliferation, an accumulation of stem cell Ag-1hi cTEC, and, in early life, a decrease in medullary TEC numbers. These alterations resulted in reduced thymic cellularity in early life, a reduction in CD4 single-positive and CD8 single-positive numbers in both young and adult mice, and enhanced peripheral CD8+ T cell survival upon TCR stimulation. Collectively, our results identify RA as a regulator of TEC homeostasis that is essential for TEC function and normal thymopoiesis.

AB - Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. In this study, we show a key in vivo role for the vitamin A metabolite, retinoic acid (RA), in TEC homeostasis. In the absence of RA signaling in TEC, cortical TEC (cTEC) and CD80loMHC class IIlo medullary TEC displayed subset-specific alterations in gene expression, which in cTEC included genes involved in epithelial proliferation, development, and differentiation. Mice whose TEC were unable to respond to RA showed increased cTEC proliferation, an accumulation of stem cell Ag-1hi cTEC, and, in early life, a decrease in medullary TEC numbers. These alterations resulted in reduced thymic cellularity in early life, a reduction in CD4 single-positive and CD8 single-positive numbers in both young and adult mice, and enhanced peripheral CD8+ T cell survival upon TCR stimulation. Collectively, our results identify RA as a regulator of TEC homeostasis that is essential for TEC function and normal thymopoiesis.

U2 - 10.4049/jimmunol.1800418

DO - 10.4049/jimmunol.1800418

M3 - Journal article

C2 - 29848752

SN - 0022-1767

VL - 201

SP - 524

EP - 532

JO - Journal of Immunology

JF - Journal of Immunology

IS - 2

ER -

Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater