Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells

Katharina Essig; Desheng Hu; Joao C. Guimaraes; Dominik Alterauge; Stephanie Edelmann; Timsse Raj; Jan Kranich; Gesine Behrens; Alexander Heiseke; Stefan Floess; Juliane Klein; Andreas Maiser; Susan Marschall; Martin Hrabe de Angelis; Heinrich Leonhardt; Cornelis F. Calkhoven; Elfriede Noessner; Thomas Brocker; Jochen Huehn; Anne B. Krug; Mihaela Zavolan; Dirk Baumjohann; Vigo Heissmeyer

doi:10.1016/j.immuni.2017.11.008

Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells

Katharina Essig, Desheng Hu, Joao C. Guimaraes, Dominik Alterauge, Stephanie Edelmann, Timsse Raj, Jan Kranich, Gesine Behrens, Alexander Heiseke, Stefan Floess, Juliane Klein, Andreas Maiser, Susan Marschall, Martin Hrabe de Angelis, Heinrich Leonhardt, Cornelis F. Calkhoven, Elfriede Noessner, Thomas Brocker, Jochen Huehn, Anne B. KrugMihaela Zavolan, Dirk Baumjohann, Vigo Heissmeyer

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

45 Citations (Scopus)

Abstract

Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 similar to 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.

Original language	English
Pages (from-to)	1067-1082.e12
Number of pages	28
Journal	Immunity
Volume	47
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2017.11.008
Publication status	Published - 19-Dec-2017

Keywords

COSTIMULATOR MESSENGER-RNA
GERMINAL CENTER REACTION
TH17 DIFFERENTIATION
EFFECTOR LINEAGE
ROR-GAMMA
EXPRESSION
MTOR
AUTOIMMUNITY
INFLAMMATION
RECEPTOR

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Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells
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Essig, K., Hu, D., Guimaraes, J. C., Alterauge, D., Edelmann, S., Raj, T., Kranich, J., Behrens, G., Heiseke, A., Floess, S., Klein, J., Maiser, A., Marschall, S., de Angelis, M. H., Leonhardt, H., Calkhoven, C. F., Noessner, E., Brocker, T., Huehn, J., ... Heissmeyer, V. (2017). Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. Immunity, 47(6), 1067-1082.e12. https://doi.org/10.1016/j.immuni.2017.11.008

Essig, Katharina ; Hu, Desheng ; Guimaraes, Joao C. ; Alterauge, Dominik ; Edelmann, Stephanie ; Raj, Timsse ; Kranich, Jan ; Behrens, Gesine ; Heiseke, Alexander ; Floess, Stefan ; Klein, Juliane ; Maiser, Andreas ; Marschall, Susan ; de Angelis, Martin Hrabe ; Leonhardt, Heinrich ; Calkhoven, Cornelis F. ; Noessner, Elfriede ; Brocker, Thomas ; Huehn, Jochen ; Krug, Anne B. ; Zavolan, Mihaela ; Baumjohann, Dirk ; Heissmeyer, Vigo. / Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. In: Immunity. 2017 ; Vol. 47, No. 6. pp. 1067-1082.e12.

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title = "Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells",

abstract = "Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 similar to 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.",

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author = "Katharina Essig and Desheng Hu and Guimaraes, {Joao C.} and Dominik Alterauge and Stephanie Edelmann and Timsse Raj and Jan Kranich and Gesine Behrens and Alexander Heiseke and Stefan Floess and Juliane Klein and Andreas Maiser and Susan Marschall and {de Angelis}, {Martin Hrabe} and Heinrich Leonhardt and Calkhoven, {Cornelis F.} and Elfriede Noessner and Thomas Brocker and Jochen Huehn and Krug, {Anne B.} and Mihaela Zavolan and Dirk Baumjohann and Vigo Heissmeyer",

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Essig, K, Hu, D, Guimaraes, JC, Alterauge, D, Edelmann, S, Raj, T, Kranich, J, Behrens, G, Heiseke, A, Floess, S, Klein, J, Maiser, A, Marschall, S, de Angelis, MH, Leonhardt, H, Calkhoven, CF, Noessner, E, Brocker, T, Huehn, J, Krug, AB, Zavolan, M, Baumjohann, D & Heissmeyer, V 2017, 'Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells', Immunity, vol. 47, no. 6, pp. 1067-1082.e12. https://doi.org/10.1016/j.immuni.2017.11.008

Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. / Essig, Katharina; Hu, Desheng; Guimaraes, Joao C.; Alterauge, Dominik; Edelmann, Stephanie; Raj, Timsse; Kranich, Jan; Behrens, Gesine; Heiseke, Alexander; Floess, Stefan; Klein, Juliane; Maiser, Andreas; Marschall, Susan; de Angelis, Martin Hrabe; Leonhardt, Heinrich; Calkhoven, Cornelis F.; Noessner, Elfriede; Brocker, Thomas; Huehn, Jochen; Krug, Anne B.; Zavolan, Mihaela; Baumjohann, Dirk; Heissmeyer, Vigo.

In: Immunity, Vol. 47, No. 6, 19.12.2017, p. 1067-1082.e12.

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

TY - JOUR

T1 - Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells

AU - Essig, Katharina

AU - Hu, Desheng

AU - Guimaraes, Joao C.

AU - Alterauge, Dominik

AU - Edelmann, Stephanie

AU - Raj, Timsse

AU - Kranich, Jan

AU - Behrens, Gesine

AU - Heiseke, Alexander

AU - Floess, Stefan

AU - Klein, Juliane

AU - Maiser, Andreas

AU - Marschall, Susan

AU - de Angelis, Martin Hrabe

AU - Leonhardt, Heinrich

AU - Calkhoven, Cornelis F.

AU - Noessner, Elfriede

AU - Brocker, Thomas

AU - Huehn, Jochen

AU - Krug, Anne B.

AU - Zavolan, Mihaela

AU - Baumjohann, Dirk

AU - Heissmeyer, Vigo

PY - 2017/12/19

Y1 - 2017/12/19

N2 - Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 similar to 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.

AB - Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 similar to 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.

KW - COSTIMULATOR MESSENGER-RNA

KW - GERMINAL CENTER REACTION

KW - TH17 DIFFERENTIATION

KW - EFFECTOR LINEAGE

KW - ROR-GAMMA

KW - EXPRESSION

KW - MTOR

KW - AUTOIMMUNITY

KW - INFLAMMATION

KW - RECEPTOR

U2 - 10.1016/j.immuni.2017.11.008

DO - 10.1016/j.immuni.2017.11.008

M3 - Article

VL - 47

SP - 1067-1082.e12

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 6

ER -