A mutation in X‐linked inhibitor of apoptosis ( G 466 X ) leads to memory inflation of Epstein–Barr virus‐specific T cells

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 ( G 466 X ) leading to a late‐truncated protein and varying clinical features, we identified gradual hypogammaglobulinaemia and large expansions of T cell subsets, including a prominent CD 4 + CD 8 + 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.