title: A mutation in X-linked inhibitor of apoptosis (G466X) leads to memory inflation of Epstein-Barr virus-specific T cells.
abstract: Mutations in the X-linked inhibitor of apoptosis (XIAP) gene have been associated with XLP-like disease, including recurrent Epstein-Barr virus (EBV)-related haemophagocytic lymphohystiocytosis (HLH), but the immunopathogenic bases of EBV-related disease in XIAP deficiency is unknown. We present the first analysis of EBV-specific T cell responses in functional XIAP deficiency. In a family of patients with a novel mutation in XIAP (G466X) leading to a late-truncated protein and varying clinical features, we identified gradual hypogammaglobulinaemia and large expansions of T cell subsets, including a prominent CD4(+) CD8(+) population. Extensive ex-vivo analyses showed that the expanded T cell subsets were dominated by EBV-specific cells with conserved cytotoxic, proliferative and interferon (IFN)-γ secretion capacity. The EBV load in blood fluctuated and was occasionally very high, indicating that the XIAP(G466X) mutation could impact upon EBV latency. XIAP deficiency may unravel a new immunopathogenic mechanism in EBV-associated disease.
authors: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors: E
authors: E
authors: Lopez-Granados
authors: M
authors: M
authors: Stacey
authors: A-K
authors: AK
authors: Kienzler
authors: S
authors: S
authors: Sierro
authors: C B
authors: CB
authors: Willberg
authors: C P
authors: CP
authors: Fox
authors: S
authors: S
authors: Rigaud
authors: H M
authors: HM
authors: Long
authors: A D
authors: AD
authors: Hislop
authors: A B
authors: AB
authors: Rickinson
authors: S
authors: S
authors: Patel
authors: S
authors: S
authors: Latour
authors: P
authors: P
authors: Klenerman
authors: H
authors: H
authors: Chapel
mesh_terms: D002478:Cells, Cultured; D006239:Haplotypes; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology*; D019562:Viral Load; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D007371:Interferon-gamma
keywords: T cells; cytotoxic T cells; immunodeficiency diseases; viral