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

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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

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: issn: 2041-1723

Keyword: Krankheit
Genetik
Immunologie

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2019

Creator: 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

DOI: 10.1038/s41467-019-10812-x

URN: urn:nbn:de:bsz:25-freidok-1502564

Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 25.03.2025, 1:44 PM CET

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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
Universität

Time of origin

2019

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

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Other Objects (12)

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

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