Lopez-Granados E., Stacey M., Kienzler A-K., Sierro S., Willberg CB., Fox CP., Rigaud S., Long HM., Hislop AD., Rickinson AB., Patel S., Latour S., Klenerman P., Chapel H.

Summary 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 XIAPG466X mutation could impact upon EBV latency. XIAP deficiency may unravel a new immunopathogenic mechanism in EBV-associated disease.

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

Lopez-Granados E., Stacey M., Kienzler A-K., Sierro S., Willberg CB., Fox CP., Rigaud S., Long HM., Hislop AD., Rickinson AB., Patel S., Latour S., Klenerman P., Chapel H.

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