Mohammed F Alosaimi1, Manfred Hoenig2, Faris Jaber3, Craig D Platt3, Jennifer Jones3, Jacqueline Wallace3, Klaus-Michael Debatin2, Ansgar Schulz2, Eva Jacobsen2, Peter Möller4, Hanan E Shamseldin5, Ferdous Abdulwahab5, Niema Ibrahim5, Hosam Alardati6, Faisal Almuhizi7, Ibraheem F Abosoudah8, Talal A Basha9, Janet Chou3, Fowzan S Alkuraya5, Raif S Geha10. 1. Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia. 2. Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany. 3. Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass. 4. Institute of Pathology, University of Ulm, Ulm, Germany. 5. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 6. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. 7. Department of Medicine, Security Force Hospital, Riyadh, Saudi Arabia. 8. Department of Oncology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. 9. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. 10. Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.
Abstract
BACKGROUND: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.
BACKGROUND: The tumorTNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.
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