Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

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

*Corresponding author for this work

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    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.
    Original languageEnglish
    Article numberji1800418
    JournalJournal of Immunology
    Volume200
    Issue number11
    Number of pages13
    ISSN0022-1767
    DOIs
    Publication statusPublished - 2018

    Cite this

    Wendland, Kerstin ; Niss, Kristoffer ; Kotarsky, Knut ; Wu, Nikita Y. H. ; White, Andrea J ; Jendholm, Johan ; Rivollier, Aymeric ; Izarzugaza, Jose M G ; Brunak, Søren ; Holländer, Georg A ; Anderson, Graham ; Sitnik, Katarzyna M. ; Agace, William Winston. / Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis. In: Journal of Immunology. 2018 ; Vol. 200, No. 11.
    @article{3b5000d6f3cf4a9aa472e37a1b515bc5,
    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 Y. H.} and White, {Andrea J} and Johan Jendholm 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 Winston}",
    year = "2018",
    doi = "10.4049/jimmunol.1800418",
    language = "English",
    volume = "200",
    journal = "Journal of Immunology",
    issn = "0022-1767",
    publisher = "American Association of Immunologists",
    number = "11",

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    Wendland, K, Niss, K, Kotarsky, K, Wu, NYH, White, AJ, Jendholm, J, Rivollier, A, Izarzugaza, JMG, Brunak, S, Holländer, GA, Anderson, G, Sitnik, KM & Agace, WW 2018, 'Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis', Journal of Immunology, vol. 200, no. 11, ji1800418. https://doi.org/10.4049/jimmunol.1800418

    Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis. / Wendland, Kerstin; Niss, Kristoffer; Kotarsky, Knut; Wu, Nikita Y. H.; White, Andrea J; Jendholm, Johan; Rivollier, Aymeric ; Izarzugaza, Jose M G; Brunak, Søren; Holländer, Georg A; Anderson, Graham; Sitnik, Katarzyna M.; Agace, William Winston.

    In: Journal of Immunology, Vol. 200, No. 11, ji1800418, 2018.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

    AU - Wendland, Kerstin

    AU - Niss, Kristoffer

    AU - Kotarsky, Knut

    AU - Wu, Nikita Y. H.

    AU - White, Andrea J

    AU - Jendholm, 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 Winston

    PY - 2018

    Y1 - 2018

    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

    VL - 200

    JO - Journal of Immunology

    JF - Journal of Immunology

    SN - 0022-1767

    IS - 11

    M1 - ji1800418

    ER -