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

Abstract

SummaryMutations 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.

Primary immunodeficiencies and the control of Epstein–Barr virus infection

“…A recent study of one XIAP kindred (albeit one also carrying a rare CD40 ligand polymorphism) has identified individuals with persistent CD8 lymphocytosis, and unusually large expansion of EBV-specific CD4 + and CD8 + T cells, in the blood many years after symptomatic primary EBV infection. 55 This is at least consistent with the idea that hyperexpansion of the EBV-induced T cell response could underlie at least some cases of XIAP-associated HLH. recently recognized through its unexpectedly high incidence of EBV-associated pathology.…”

“…By contrast, NK cell numbers and 2B4‐dependent effector function appear to be normal in XIAP patients, as are circulating T cell numbers despite the fact that T cells are more sensitive to apoptosis‐inducing signals in vitro . A recent study of one XIAP kindred (albeit one also carrying a rare CD40 ligand polymorphism) has identified individuals with persistent CD8 lymphocytosis, and unusually large expansion of EBV‐specific CD4 + and CD8 + T cells, in the blood many years after symptomatic primary EBV infection . This is at least consistent with the idea that hyperexpansion of the EBV‐induced T cell response could underlie at least some cases of XIAP‐associated HLH.…”

The (gradual) rise of memory inflation

“…These features of CD8 + T‐cell responses have been observed in other infection settings such as chronic norovirus infection in mice,41 and some extreme responses to Epstein Barr Virus (EBV infection) in humans 42. Such responses, as well as those induced by adenoviral vectored vaccines in humans could be called “inflation‐like”.…”

T-Cell Responses to EBV

“…Similarly, patients with mutations in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP), show sensitivity to EBV infection and have low numbers of iNKT cells (Rigaud et al 2006). These patients have normal numbers of T cells; however, these are more sensitive to apoptotic stimuli, again making it unclear whether iNKT numbers are the solely responsible for controlling disease (Lopez-Granados et al 2014). Other models and observations hint to a role of iNKT cells: patients with EBV-associated malignancies have lower circulating numbers of these cells, while iNKT cells adoptively transferred into immunodeficient mice then challenged with EBV-related malignant cells show reduced tumour formation (Yuling et al 2009).…”