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J Allergy Clin Immunol ; 144(2): 574-583.e5, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30872117

RESUMO

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.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Transtornos Linfoproliferativos/imunologia , Mutação de Sentido Incorreto , Doenças da Imunodeficiência Primária/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Pré-Escolar , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/virologia , Masculino , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/patologia , Doenças da Imunodeficiência Primária/virologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Sequenciamento do Exoma
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