Ahmet Eken1,2, Murat Cansever3, Fatma Zehra Okus1,2, Serife Erdem1,2, Ercan Nain4, Zehra Busra Azizoglu1,2, Yesim Haliloglu1,2, Musa Karakukcu3, Alper Ozcan3, Omer Devecioglu5, Guzide Aksu6, Zeynep Arikan Ayyildiz7, Erdem Topal8, Elif Karakoc Aydiner9,10, Ayca Kiykim9,10, Ayse Metin11, Funda Cipe12, Aysenur Kaya13, Hasibe Artac14, Ismail Reisli15, Sukru N Guner15, Vedat Uygun16, Gulsun Karasu16, Hamiyet Dönmez Altuntas1, Halit Canatan1,2, Mohamed Oukka17, Ahmet Ozen9,10, Talal A Chatila18,19, Sevgi Keles15, Safa Baris9,10, Ekrem Unal3, Turkan Patiroglu3. 1. Department of Medical Biology, Erciyes University School of Medicine, Kayseri, Turkey. 2. Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, Turkey. 3. Departments of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University School of Medicine, Kayseri, Turkey. 4. Sanliurfa Ministry of Health Training and Research Hospital, Sanliurfa, Turkey. 5. Department of Pediatric Hematology and Oncology, Memorial Atasehir Hospital, Istanbul, Turkey. 6. Department of Pediatric Rheumatology, Ege University, Izmir, Turkey. 7. Department of Pediatrics, Medical Park Izmir Hospital, Izmir, Turkey. 8. Department of Allergy, School of Medicine, Inonu University, Malatya, Turkey. 9. Department of Pediatrics, Division of Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey. 10. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. 11. Department of Pediatric Allergy and Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey. 12. Kanuni Sultan Suleyman Training and Research Hospital, Istanbul Health Sciences University, Istanbul, Turkey. 13. Division of Pediatric Allergy and Immunology, Istinye University, Istanbul, Turkey. 14. Department of Pediatrics, Division of Allergy and Immunology, Selcuk University School of Medicine, Konya, Turkey. 15. Meram School of Medicine, Division of Pediatric Allergy and Immunology, Necmettin Erbakan University, Konya, Turkey. 16. Department of Pediatric Bone Marrow Transplantation Unit, Medical Park Antalya Hospital, Antalya, Turkey. 17. Department of Immunology, University of Washington, Seattle, WA, USA. 18. Division of Immunology, Boston Children's Hospital, Boston, MA, USA. 19. Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Abstract
BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. METHODS: Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. RESULTS: DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. CONCLUSION: DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.
BACKGROUND:Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. METHODS: Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. RESULTS:DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. CONCLUSION:DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.
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Authors: Joëlle Khourieh; Peng Zhang; Franck Rapaport; Qian Zhang; Anne Puel; Vivien Béziat; Jean-Laurent Casanova; Bertrand Boisson; Takaki Asano; András N Spaan; Juan Li; Wei-Te Lei; Simon J Pelham; David Hum; Maya Chrabieh; Ji Eun Han; Antoine Guérin; Joseph Mackie; Sudhir Gupta; Biman Saikia; Jamila E I Baghdadi; Ilham Fadil; Aziz Bousfiha; Tanwir Habib; Nico Marr; Luckshman Ganeshanandan; Jane Peake; Luke Droney; Andrew Williams; Fatih Celmeli; Nevin Hatipoglu; Tayfun Ozcelik; Capucine Picard; Laurent Abel; Stuart G Tangye; Stéphanie Boisson-Dupuis Journal: J Exp Med Date: 2021-06-17 Impact factor: 14.307