STX11 p.R129P variant correlate with an in vitro impairment in NK and CD8+ T-cell-mediated cytotoxicity

STX11 encodes a t-SNARE protein essential for the final fusion of lytic granules with the plasma membrane of NK and CD8+ T-cells. Biallelic mutations in STX11 have been associated with familial hemophagocytic lymphohistiocytosis (FHL) type 4. Here, we analyzed the functional relevance of an heterozygous STX11 variant (p.R129P) identified in a pediatric patient diagnosed with Evans syndrome. Structural analysis suggested that the proline replacement at position 129 could impact key protein-protein interaction with Munc18-2. We found that patient’ cells carrying p.R129P mutation showed a decrease in NK-cell degranulation and cytotoxicity, and in CD8+ T-cell degranulation as compared to healthy donors. In vitro treatment of patient derived cells with IL-2, restored both functions to levels comparable as those observed in healthy donors. We also observed reduced STX11 protein expression in patient PBMC’s and impaired TLR4 re-localization in the patient's monocytes. Our findings provide evidence for the pathogenic role of the p.R129P-STX11 variant, and suggest that aberrant NK-cell and T-cell function may contribute to the development of autoimmune disorders.