TY - JOUR
T1 - Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis
AU - Serwas, Nina K.
AU - Hoeger, Birgit
AU - Ardy, Rico C.
AU - Stulz, Sigrun V.
AU - Sui, Zhenhua
AU - Memaran, Nima
AU - Meeths, Marie
AU - Krolo, Ana
AU - Yüce Petronczki, Özlem
AU - Pfajfer, Laurène
AU - Hou, Tie Z.
AU - Halliday, Neil
AU - Santos-Valente, Elisangela
AU - Kalinichenko, Artem
AU - Kennedy, Alan
AU - Mace, Emily M.
AU - Mukherjee, Malini
AU - Tesi, Bianca
AU - Schrempf, Anna
AU - Loizou, Joanna I.
AU - Kain, Renate
AU - Bidmon-Fliegenschnee, Bettina
AU - Schickel, Jean Nicolas
AU - Glauzy, Salomé
AU - Huemer, Jakob
AU - Garncarz, Wojciech
AU - Salzer, Elisabeth
AU - Pierides, Iro
AU - Bilic, Ivan
AU - Thiel, Jens
AU - Priftakis, Peter
AU - Banerjee, Pinaki P.
AU - Förster-Waldl, Elisabeth
AU - Medgyesi, David
AU - Huber, Wolf Dietrich
AU - Orange, Jordan S.
AU - Meffre, Eric
AU - Sansom, David M.
AU - Bryceson, Yenan T.
AU - Altman, Amnon
AU - Boztug, Kaan
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-10812-x
DO - 10.1038/s41467-019-10812-x
M3 - Article
C2 - 31308374
AN - SCOPUS:85069039623
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3106
ER -