T and NK cell functionality in a patient harboring heterozygous novel BCL11B p.Asp632fsAla∗91 and STX11 p.R129P mutations

BCL11B is a transcription factor essential for central nervous system development and T-cell differentiation that regulates numerous genes across various pathways. Heterozygous BCL11B defects can lead to a broad spectrum of phenotypes, including neurological disorders with or without immunological features. STX11 encodes a t-SNARE protein crucial for the final fusion of lytic granules with the plasma membrane of NK-cells and CD8⁺ T-cells. Biallelic mutations in STX11 are linked to familial hemophagocytic lymphohistiocytosis type 4. We analyzed the functional impact of heterozygous BCL11B (p.Asp632fsAla∗91) and STX11 (p.R129P) variants present in a pediatric patient with Evans syndrome and neurodevelopmental delay, without hemophagocytic lymphohistiocytosis presentation. The BCL11B p.Asp632fsAla∗91 variant, positioned to escape nonsense-mediated decay, likely produces a truncated protein losing three zinc finger domains. Given that BCL11B is involved in the activation of IL-2 gene expression, we evaluated this function and found a reduced IL-2 production by the patient's CD4⁺ T-cells. On the other hand, structural analysis of STX11 indicated that the proline substitution at position 129 could disrupt key interactions with Munc18-2. The patient's cells exhibited decreased NK-cell degranulation and cytotoxicity, and diminished CD8⁺ T-cell degranulation compared to healthy donors. <i>In vitro</i> IL-2 treatment restored these functions to healthy donor levels. We also observed a reduced STX11 protein expression in patient PBMCs. We hypothesize that impaired IL-2 secretion caused by the BCL11B mutation may reduce the patient's ability to compensate for STX11 dysfunction, suggesting that the combined effect of BCL11B and STX11 mutations contributes to the observed immune dysfunction and the patient's complex phenotype. Additionally, our findings suggest that abnormal NK- and T-cells function could play a role in the onset of autoimmune disorders.