Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis

Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman and Kaan Boztug ()
Additional contact information
Nina K. Serwas: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Birgit Hoeger: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Rico C. Ardy: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Sigrun V. Stulz: Karolinska University Hospital Huddinge
Zhenhua Sui: La Jolla Institute for Allergy & Immunology
Nima Memaran: Medical University of Vienna
Marie Meeths: Karolinska University Hospital Solna
Ana Krolo: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Özlem Yüce Petronczki: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Laurène Pfajfer: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Tie Z. Hou: University College London
Neil Halliday: University College London
Elisangela Santos-Valente: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Artem Kalinichenko: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Alan Kennedy: University College London
Emily M. Mace: Texas Children’s Hospital
Malini Mukherjee: Texas Children’s Hospital
Bianca Tesi: Karolinska University Hospital Solna
Anna Schrempf: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Winfried F. Pickl: Medical University of Vienna
Joanna I. Loizou: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Renate Kain: Medical University of Vienna
Bettina Bidmon-Fliegenschnee: Medical University of Vienna
Jean-Nicolas Schickel: Yale University School of Medicine
Salomé Glauzy: Yale University School of Medicine
Jakob Huemer: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Wojciech Garncarz: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Elisabeth Salzer: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Iro Pierides: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Ivan Bilic: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Jens Thiel: University Medical Center Freiburg
Peter Priftakis: Karolinska University Hospital Huddinge
Pinaki P. Banerjee: Texas Children’s Hospital
Elisabeth Förster-Waldl: Medical University of Vienna
David Medgyesi: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Wolf-Dietrich Huber: Medical University of Vienna
Jordan S. Orange: Texas Children’s Hospital
Eric Meffre: Yale University School of Medicine
David M. Sansom: University College London
Yenan T. Bryceson: Karolinska University Hospital Huddinge
Amnon Altman: La Jolla Institute for Allergy & Immunology
Kaan Boztug: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.

Date: 2019
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DOI: 10.1038/s41467-019-10812-x

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