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

Autor:	Serwas NK; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Department of Pathology, University of California San Francisco, San Francisco, CA, USA., Hoeger B; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria., Ardy RC; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Stulz SV; Centre for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden., Sui Z; Division of Cell Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA., Memaran N; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.; Centre for Paediatrics and Adoloscent Medicine, Hannover Medical School, Hannover, Germany., Meeths M; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden., Krolo A; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Yüce Petronczki Ö; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Pfajfer L; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Center for Pathophysiology of Toulouse Purpan, INSERM UMR1043, CNRS UMR5282, Paul Sabatier University, Toulouse, France., Hou TZ; Institute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK., Halliday N; Institute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK., Santos-Valente E; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Kalinichenko A; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Kennedy A; Institute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK., Mace EM; Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.; Columbia University Medical Center, Columbia, NY, USA., Mukherjee M; Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA., Tesi B; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden., Schrempf A; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Pickl WF; Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria., Loizou JI; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Kain R; Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria., Bidmon-Fliegenschnee B; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria., Schickel JN; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06511, USA., Glauzy S; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06511, USA., Huemer J; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Garncarz W; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Salzer E; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Pierides I; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Bilic I; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Takeda (Shire), Vienna, Austria., Thiel J; Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, 79106, Germany., Priftakis P; Astrid Lindgren Children's Hospital, Karolinska University Hospital Huddinge, Stockholm, Sweden., Banerjee PP; Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.; MD Anderson Cancer Center, Houston, TX, USA., Förster-Waldl E; Department of Pediatrics and Adolescent Medicine, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Vienna, Austria., Medgyesi D; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Huber WD; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria., Orange JS; Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.; Columbia University Medical Center, Columbia, NY, USA., Meffre E; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06511, USA., Sansom DM; Institute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK., Bryceson YT; Centre for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden., Altman A; Division of Cell Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA., Boztug K; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. kaan.boztug@ccri.at.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. kaan.boztug@ccri.at.; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. kaan.boztug@ccri.at.; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. kaan.boztug@ccri.at.; St. Anna Kinderspital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. kaan.boztug@ccri.at.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Jul 15; Vol. 10 (1), pp. 3106. Date of Electronic Publication: 2019 Jul 15.
DOI:	10.1038/s41467-019-10812-x
Abstrakt:	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.
Databáze:	MEDLINE
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