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

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

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: issn: 2041-1723

Klassifikation und Themen

• Schlagwort: Krankheit ; Genetik ; Immunologie

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2019
• Urheber: Serwas, Nina K. ; Höger, Birgit ; Ardy, Rico C. ; Stulz, Sigrun V. ; Sui, Zhenhua ; Memaran, Nima ; Meeths, Marie ; Krolo, Ana ; Yüce Petronczki, Özlem ; Pfajfer, Laurène ; Hou, Tie Zheng ; Halliday, Neil ; Santos-Valente, Elisangela ; Kalinichenko, Artem ; Kennedy, Alan ; Mace, Emily M. ; Mukherjee, Malini ; Tesi, Bianca ; Schrempf, Anna ; Loizou, Joanna I. ; Kain, Renate ; Bidmon-Fliegenschnee, Bettina ; Schickel, Jean-Nicolas ; Glauzy, Salomé ; Huemer, Jakob ; Garncarz, Wojciech ; Salzer, Elisabeth ; Pierides, Iro ; Bilic, Ivan ; Thiel, Jens ; Priftakis, Peter ; Banerjee, Pinaki P. ; Förster-Waldl, Elisabeth ; Medgyesi, David ; Huber, Wolf-Dietrich ; Orange, Jordan ; Meffre, Eric ; Sansom, David M. ; Bryceson, Yenan T. ; Altman, Amnon ; Boztug, Kaan

Weitere Informationen

• DOI: 10.1038/s41467-019-10812-x
• URN: urn:nbn:de:bsz:25-freidok-1502564
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:44 MEZ