Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 178, Issue 3, Pages 470-482Publisher
WILEY
DOI: 10.1111/cei.12427
Keywords
cytotoxic T cells; immunodeficiency diseases; T cells; viral
Categories
Funding
- NIHR Oxford Biomedical Research Centre Programme
- UK Primary Immunodeficiency Association (PIA) Center of Excellence award
- Jeffrey Model Foundation NYC
- Baxter Healthcare LA
- Oxfordshire Health Service Research Committee
- MRC [G0901755] Funding Source: UKRI
- Medical Research Council [G0901755] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10204] Funding Source: researchfish
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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)- 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.
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