A mutation in X-linked inhibitor of apoptosis (G466X) leads to memory inflation of Epstein-Barr virus-specific T cells

Clin Exp Immunol. 2014 Dec;178(3):470-82. doi: 10.1111/cei.12427.

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.

Keywords: T cells; cytotoxic T cells; immunodeficiency diseases; viral.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Haplotypes
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Immunologic Memory*
  • Interferon-gamma / biosynthesis
  • Mutation*
  • T-Lymphocytes / immunology*
  • Viral Load
  • X-Linked Inhibitor of Apoptosis Protein / genetics*

Substances

  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Interferon-gamma