Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Alosaimi, Mohammed F.^1,2,3  Hoenig, Manfred⁴  Jaber, Faris^1,2  Platt, Craig D.^1,2  Jones, Jennifer^1,2  Wallace, Jacqueline^1,2  Debatin, Klaus-Michael⁴  Schulz, Ansgar⁴  Jacobsen, Eva⁴  Moller, Peter⁵  Shamseldin, Hanan E.⁶  Abdulwahab, Ferdous⁶  Ibrahim, Niema⁶  Alardati, Hosam⁷  Almuhizi, Faisal¹⁰  Abosoudah, Ibraheem F.⁸  Basha, Talal A.⁹  Chou, Janet^1,2  Alkuraya, Fowzan S.⁶  Geha, Raif S.^1,2 

[1] Boston Childrens Hosp, Div Immunol, 1 Blackfan Circle,Karp Bldg 10th Floor, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[3] King Saud Univ, Dept Pediat, Riyadh, Saudi Arabia

[4] Univ Med Ctr Ulm, Dept Pediat & Adolescent Med, Ulm, Germany

[5] Univ Ulm, Inst Pathol, Ulm, Germany

[6] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia

[7] King Faisal Specialist Hosp & Res Ctr, Dept Pathol & Lab Med, Jeddah, Saudi Arabia

[8] King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Jeddah, Saudi Arabia

[9] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Jeddah, Saudi Arabia

[10] Secur Force Hosp, Dept Med, Riyadh, Saudi Arabia

关键词: 4-1BB;    CD137;    immunodeficiency;    EBV;    Hodgkin lymphoma;   

DOI  :  10.1016/j.jaci.2019.03.002

来源: Elsevier

【 摘 要 】

Background: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated Tcells. 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-gamma 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.

【 授权许可】

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