Early hyperactivation and activation-associated mitochondrial abnormalities in GATA2 deficiency

Περίληψη

Background Germline GATA2 deficiency is a hereditary disorder characterized by immunodeficiency, bone marrow failure, and a high risk of myelodysplastic neoplasms and acute myeloid leukemia (AML). Although abnormalities of innate immunity are well recognized, the phenotype and functional state of CD8 + T cells remain incompletely characterized. Methods We performed integrated phenotypic, transcriptional, metabolic, functional, and ultrastructural analyses of peripheral blood cells from six non-transplanted GATA2-deficient patients without ongoing AML, combining CD8 + T-cell-specific immunophenotyping and mass cytometry with bulk cytokine-induced killer (CIK) differentiation and complementary metabolic and mitochondrial assays. We additionally performed single-cell transcriptomic analysis of a previously published gata2b +/− zebrafish model. Results GATA2-deficient CD8 + T cells exhibited contraction of the central memory compartment. Transcriptomic and mass cytometric analyses demonstrated increased activation and cell-cycle programs. Despite preserved short-term cytotoxicity, sustained CIK differentiation was accompanied by metabolic and mitochondrial abnormalities, including lower respiratory reserve at day 6, broader reductions in respiratory parameters by day 14, higher basal extracellular acidification at day 6, increased mitochondrial content with reduced membrane-potential-dependent activity, and mitochondrial ultrastructural remodeling. Increased expression of glycolytic and mitochondrial remodeling-associated proteins supported a coordinated remodeling of metabolic pathways during activation. Similar inflammatory and metabolic transcriptional signatures were identified in gata2b +/− zebrafish T cells, providing supportive cross-species evidence. Conclusions GATA2 deficiency is associated with an activated CD8 + T-cell phenotype accompanied, during sustained CIK differentiation, by progressive metabolic and mitochondrial abnormalities. These findings identify impaired metabolic fitness as a previously underrecognized component of T-cell dysfunction in GATA2 deficiency.