Severe combined immunodeficiency in Sting V154M/WT mice

Delphine Bouis; Peggy Kirstetter; Florent Arbogast; Delphine Lamon; Virginia Delgado; Sophie Jung; Claudine Ebel; Hugues Jacobs; Anne-Marie Knapp; Nadia Jeremiah; Alexandre Belot; Thierry Martin; Yanick J Crow; Isabelle André-Schmutz; Anne-Sophie Korganow; Frédéric Rieux-Laucat; Pauline Soulas-Sprauel

doi:10.1016/j.jaci.2018.04.034

Severe combined immunodeficiency in Sting V154M/WT mice

Delphine Bouis, Peggy Kirstetter, Florent Arbogast, Delphine Lamon, Virginia Delgado, Sophie Jung, Claudine Ebel, Hugues Jacobs, Anne-Marie Knapp, Nadia Jeremiah, Alexandre Belot, Thierry Martin, Yanick J Crow, Isabelle André-Schmutz, Anne-Sophie Korganow, Frédéric Rieux-Laucat, Pauline Soulas-Sprauel

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

Abstract

BACKGROUND: Autosomal dominant gain-of-function (GOF) mutations in human STING (Stimulator of Interferon Genes) lead to a severe autoinflammatory disease called SAVI (STING Associated Vasculopathy with onset in Infancy), associated with enhanced expression of interferon (IFN) stimulated gene (ISG) transcripts.

OBJECTIVE: The goal of this study was to analyze the phenotype of a new mouse model of Sting hyperactivation, and the role of type I IFN in this system.

METHODS: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse Sting, corresponding to a recurrent mutation seen in human patients with SAVI. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. Sting V154M/WT mice were crossed to IFNAR (IFNα/β Receptor) knock-out mice in order to evaluate the type I IFN-dependence of the mutant Sting phenotype recorded.

RESULTS: In Sting V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T and NK cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B and T cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Whilst the V154M/WT mutant demonstrated increased expression of ISGs, the SCID phenotype was not reversed in Sting V154M/WT IFNAR knock-out mice. However, the anti-proliferative defect in T cells was partially rescued by IFNAR deficiency.

CONCLUSIONS: Sting GOF mice developed an IFN-independent SCID phenotype with a T, B and NK cell developmental defect and hypogammaglobulinemia, associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was, partially, IFN-dependent.

Original language	English
Journal	Journal of Allergy and Clinical Immunology
Early online date	23 May 2018
DOIs	https://doi.org/10.1016/j.jaci.2018.04.034
Publication status	E-pub ahead of print - 23 May 2018

Access to Document

10.1016/j.jaci.2018.04.034

Article Sting mice 06.10.17_YJC AAM
© 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Accepted author manuscript, 72.8 KBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Cite this

Bouis, D., Kirstetter, P., Arbogast, F., Lamon, D., Delgado, V., Jung, S., Ebel, C., Jacobs, H., Knapp, A-M., Jeremiah, N., Belot, A., Martin, T., Crow, Y. J., André-Schmutz, I., Korganow, A-S., Rieux-Laucat, F., & Soulas-Sprauel, P. (2018). Severe combined immunodeficiency in Sting V154M/WT mice. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2018.04.034

Bouis, Delphine ; Kirstetter, Peggy ; Arbogast, Florent ; Lamon, Delphine ; Delgado, Virginia ; Jung, Sophie ; Ebel, Claudine ; Jacobs, Hugues ; Knapp, Anne-Marie ; Jeremiah, Nadia ; Belot, Alexandre ; Martin, Thierry ; Crow, Yanick J ; André-Schmutz, Isabelle ; Korganow, Anne-Sophie ; Rieux-Laucat, Frédéric ; Soulas-Sprauel, Pauline. / Severe combined immunodeficiency in Sting V154M/WT mice. In: Journal of Allergy and Clinical Immunology. 2018.

@article{626b1584b9f34a18a57ad2c971655cd9,

title = "Severe combined immunodeficiency in Sting V154M/WT mice",

abstract = "BACKGROUND: Autosomal dominant gain-of-function (GOF) mutations in human STING (Stimulator of Interferon Genes) lead to a severe autoinflammatory disease called SAVI (STING Associated Vasculopathy with onset in Infancy), associated with enhanced expression of interferon (IFN) stimulated gene (ISG) transcripts.OBJECTIVE: The goal of this study was to analyze the phenotype of a new mouse model of Sting hyperactivation, and the role of type I IFN in this system.METHODS: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse Sting, corresponding to a recurrent mutation seen in human patients with SAVI. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. Sting V154M/WT mice were crossed to IFNAR (IFNα/β Receptor) knock-out mice in order to evaluate the type I IFN-dependence of the mutant Sting phenotype recorded.RESULTS: In Sting V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T and NK cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B and T cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Whilst the V154M/WT mutant demonstrated increased expression of ISGs, the SCID phenotype was not reversed in Sting V154M/WT IFNAR knock-out mice. However, the anti-proliferative defect in T cells was partially rescued by IFNAR deficiency.CONCLUSIONS: Sting GOF mice developed an IFN-independent SCID phenotype with a T, B and NK cell developmental defect and hypogammaglobulinemia, associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was, partially, IFN-dependent.",

author = "Delphine Bouis and Peggy Kirstetter and Florent Arbogast and Delphine Lamon and Virginia Delgado and Sophie Jung and Claudine Ebel and Hugues Jacobs and Anne-Marie Knapp and Nadia Jeremiah and Alexandre Belot and Thierry Martin and Crow, {Yanick J} and Isabelle Andr{\'e}-Schmutz and Anne-Sophie Korganow and Fr{\'e}d{\'e}ric Rieux-Laucat and Pauline Soulas-Sprauel",

note = "Copyright {\textcopyright} 2018. Published by Elsevier Inc.",

year = "2018",

month = may,

day = "23",

doi = "10.1016/j.jaci.2018.04.034",

language = "English",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

}

Severe combined immunodeficiency in Sting V154M/WT mice. / Bouis, Delphine; Kirstetter, Peggy; Arbogast, Florent; Lamon, Delphine; Delgado, Virginia; Jung, Sophie; Ebel, Claudine; Jacobs, Hugues; Knapp, Anne-Marie; Jeremiah, Nadia; Belot, Alexandre; Martin, Thierry; Crow, Yanick J; André-Schmutz, Isabelle; Korganow, Anne-Sophie; Rieux-Laucat, Frédéric; Soulas-Sprauel, Pauline.

In: Journal of Allergy and Clinical Immunology, 23.05.2018.

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

TY - JOUR

T1 - Severe combined immunodeficiency in Sting V154M/WT mice

AU - Bouis, Delphine

AU - Kirstetter, Peggy

AU - Arbogast, Florent

AU - Lamon, Delphine

AU - Delgado, Virginia

AU - Jung, Sophie

AU - Ebel, Claudine

AU - Jacobs, Hugues

AU - Knapp, Anne-Marie

AU - Jeremiah, Nadia

AU - Belot, Alexandre

AU - Martin, Thierry

AU - Crow, Yanick J

AU - André-Schmutz, Isabelle

AU - Korganow, Anne-Sophie

AU - Rieux-Laucat, Frédéric

AU - Soulas-Sprauel, Pauline

PY - 2018/5/23

Y1 - 2018/5/23

N2 - BACKGROUND: Autosomal dominant gain-of-function (GOF) mutations in human STING (Stimulator of Interferon Genes) lead to a severe autoinflammatory disease called SAVI (STING Associated Vasculopathy with onset in Infancy), associated with enhanced expression of interferon (IFN) stimulated gene (ISG) transcripts.OBJECTIVE: The goal of this study was to analyze the phenotype of a new mouse model of Sting hyperactivation, and the role of type I IFN in this system.METHODS: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse Sting, corresponding to a recurrent mutation seen in human patients with SAVI. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. Sting V154M/WT mice were crossed to IFNAR (IFNα/β Receptor) knock-out mice in order to evaluate the type I IFN-dependence of the mutant Sting phenotype recorded.RESULTS: In Sting V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T and NK cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B and T cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Whilst the V154M/WT mutant demonstrated increased expression of ISGs, the SCID phenotype was not reversed in Sting V154M/WT IFNAR knock-out mice. However, the anti-proliferative defect in T cells was partially rescued by IFNAR deficiency.CONCLUSIONS: Sting GOF mice developed an IFN-independent SCID phenotype with a T, B and NK cell developmental defect and hypogammaglobulinemia, associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was, partially, IFN-dependent.

AB - BACKGROUND: Autosomal dominant gain-of-function (GOF) mutations in human STING (Stimulator of Interferon Genes) lead to a severe autoinflammatory disease called SAVI (STING Associated Vasculopathy with onset in Infancy), associated with enhanced expression of interferon (IFN) stimulated gene (ISG) transcripts.OBJECTIVE: The goal of this study was to analyze the phenotype of a new mouse model of Sting hyperactivation, and the role of type I IFN in this system.METHODS: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse Sting, corresponding to a recurrent mutation seen in human patients with SAVI. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. Sting V154M/WT mice were crossed to IFNAR (IFNα/β Receptor) knock-out mice in order to evaluate the type I IFN-dependence of the mutant Sting phenotype recorded.RESULTS: In Sting V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T and NK cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B and T cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Whilst the V154M/WT mutant demonstrated increased expression of ISGs, the SCID phenotype was not reversed in Sting V154M/WT IFNAR knock-out mice. However, the anti-proliferative defect in T cells was partially rescued by IFNAR deficiency.CONCLUSIONS: Sting GOF mice developed an IFN-independent SCID phenotype with a T, B and NK cell developmental defect and hypogammaglobulinemia, associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was, partially, IFN-dependent.

U2 - 10.1016/j.jaci.2018.04.034

DO - 10.1016/j.jaci.2018.04.034

M3 - Article

C2 - 29800647

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

ER -

Severe combined immunodeficiency in Sting V154M/WT mice

Abstract

Access to Document

Fingerprint

Cite this