Journal Article

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

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

2019

Overview

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. CTLA-4 is critical for balancing protective immunity with self-tolerance. Here the authors identify homozygous DEF6 mutations in patients with severe autoimmunity, one of which received and responds to CTLA-4-Ig, and show that DEF6 is crucial for CTLA-4 cell surface trafficking and immune regulatory function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 13/95 / 14/63 / 38/23 / 42/41 / 45/23 / 631/208 / 631/250 / 692/699 / Autoimmune diseases / B7-1 Antigen - metabolism / Cell surface / CTLA-4 Antigen - metabolism / CTLA-4 protein / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - genetics / DNA-Binding Proteins - immunology / Gene Knockout Techniques / Guanine / Guanine nucleotide exchange factor / Guanine Nucleotide Exchange Factors - deficiency / Guanine Nucleotide Exchange Factors - genetics / Guanine Nucleotide Exchange Factors - immunology / Guanosine triphosphatases / Homeostasis / Homology / Humanities and Social Sciences / Humans / Immunity / Immunodeficiency / Immunoglobulins / Jurkat Cells / Lymphocytes / Lymphocytes T / Molecular modelling / multidisciplinary / Mutation / Nucleotides / Primary Immunodeficiency Diseases - genetics / rab GTP-Binding Proteins - genetics / rab GTP-Binding Proteins - metabolism / Remission / Science / Science (multidisciplinary) / T-Lymphocytes - metabolism / T-Lymphocytes - physiology