ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation

Erica L. Stone, Marion Pepper, Carol D. Katayama, Yann M. Kerdiles, Chen-Yen Lai, Elizabeth Emslie, Yin C. Lin, Edward Yang, Ananda W. Goldrath, Ming O. Li, Doreen A. Cantrell, Stephen M. Hedrick (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    91 Citations (Scopus)

    Abstract

    T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1-/- GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.

    Original languageEnglish
    Pages (from-to)239-251
    Number of pages13
    JournalImmunity
    Volume42
    Issue number2
    DOIs
    Publication statusPublished - 17 Feb 2015

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    Helper-Inducer T-Lymphocytes
    Cell Differentiation
    Transcription Factors
    Germinal Center
    1-Phosphatidylinositol 4-Kinase
    Immunoglobulin Isotypes
    Ligands
    Gene Expression
    Population
    Genes

    Cite this

    Stone, E. L., Pepper, M., Katayama, C. D., Kerdiles, Y. M., Lai, C-Y., Emslie, E., ... Hedrick, S. M. (2015). ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity, 42(2), 239-251. https://doi.org/10.1016/j.immuni.2015.01.017
    Stone, Erica L. ; Pepper, Marion ; Katayama, Carol D. ; Kerdiles, Yann M. ; Lai, Chen-Yen ; Emslie, Elizabeth ; Lin, Yin C. ; Yang, Edward ; Goldrath, Ananda W. ; Li, Ming O. ; Cantrell, Doreen A. ; Hedrick, Stephen M. / ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. In: Immunity. 2015 ; Vol. 42, No. 2. pp. 239-251.
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    abstract = "T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1-/- GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.",
    author = "Stone, {Erica L.} and Marion Pepper and Katayama, {Carol D.} and Kerdiles, {Yann M.} and Chen-Yen Lai and Elizabeth Emslie and Lin, {Yin C.} and Edward Yang and Goldrath, {Ananda W.} and Li, {Ming O.} and Cantrell, {Doreen A.} and Hedrick, {Stephen M.}",
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    Stone, EL, Pepper, M, Katayama, CD, Kerdiles, YM, Lai, C-Y, Emslie, E, Lin, YC, Yang, E, Goldrath, AW, Li, MO, Cantrell, DA & Hedrick, SM 2015, 'ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation', Immunity, vol. 42, no. 2, pp. 239-251. https://doi.org/10.1016/j.immuni.2015.01.017

    ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. / Stone, Erica L.; Pepper, Marion; Katayama, Carol D.; Kerdiles, Yann M.; Lai, Chen-Yen; Emslie, Elizabeth; Lin, Yin C.; Yang, Edward; Goldrath, Ananda W.; Li, Ming O.; Cantrell, Doreen A.; Hedrick, Stephen M. (Lead / Corresponding author).

    In: Immunity, Vol. 42, No. 2, 17.02.2015, p. 239-251.

    Research output: Contribution to journalArticle

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    AU - Stone, Erica L.

    AU - Pepper, Marion

    AU - Katayama, Carol D.

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    AU - Lai, Chen-Yen

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    AU - Lin, Yin C.

    AU - Yang, Edward

    AU - Goldrath, Ananda W.

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    AU - Cantrell, Doreen A.

    AU - Hedrick, Stephen M.

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    AB - T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1-/- GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.

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