ClinVar

In 2 unrelated children, each born of consanguineous families, with immunodeficiency-109 with EBV-induced lymphoproliferation (IMD109; 620282), Alosaimi et al. (2019) identified a homozygous c.325G-A transition (c.325G-A, NM_001561) in the TNFRSF9 gene, resulting in a gly109-to-ser (G109S) substitution at a highly conserved residue, in the third cysteine-rich domain (CRD) of the extracellular region but that does not directly interact with the TNFSF9 (606182) ligand. Patient white cells showed no expression of the mutant TNFRSF9 protein after stimulation compared to control cells, which upregulated TNFRSF9 expression after stimulation. In addition, the TNFSF9 ligand bound to T cells from controls, but not T cells from the patients, also consistent with a lack of expression of the mutant protein. Detailed in vitro studies showed that patient CD8+ T cells did not proliferate and had reduced expression of gamma-IFN (147570) and perforin (170280) compared to controls. The cytotoxic activity of patient CD8+ T cells against EBV-infected B cells was significantly reduced compared to controls. Treatment of normal T cells with an inhibitory anti-4-1BB antibody recapitulated the findings in patient cells. The findings supported a critical role for TNFRSF9 in the expansion and function of EBV-specific CD8+ T cells. Patient T cells also showed impaired mitochondrial biogenesis and function.