Early hyperactivation and activation-associated mitochondrial abnormalities in GATA2 deficiency
Abstract
BackgroundGermline 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.MethodsWe 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.ResultsGATA2-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.ConclusionsGATA2 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.
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BibTeX
@article{penco2026early,
title = {{Early hyperactivation and activation-associated mitochondrial abnormalities in GATA2 deficiency}},
author = {Marta Penco and Martina Maria Capelletti and Lorenzo Manfreda and Martina Failla and Stefano Rebellato and Domenico Gaspari and Lisa Mercadante and Martina Basilico and Giusi Melita and Rebecca Fumagalli and Grazia Fazio and Mario Mauri and Mario Bossi and Iris J.A. Peters and Katia Girardi and Francesco Licciardi and Carmelo Gurnari and Enrico Attardi and Guido A. Cavaletti and Adriana C. Balduzzi and Emma De Pater and Andrea Biondi and Angela M. Savino and Jolanda Sarno and Sarah Tettamanti and Francesco Saettini},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1960580},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960580},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Early hyperactivation and activation-associated mitochondrial abnormalities in GATA2 deficiency
AU - Marta Penco
AU - Martina Maria Capelletti
AU - Lorenzo Manfreda
AU - Martina Failla
AU - Stefano Rebellato
AU - Domenico Gaspari
AU - Lisa Mercadante
AU - Martina Basilico
AU - Giusi Melita
AU - Rebecca Fumagalli
AU - Grazia Fazio
AU - Mario Mauri
AU - Mario Bossi
AU - Iris J.A. Peters
AU - Katia Girardi
AU - Francesco Licciardi
AU - Carmelo Gurnari
AU - Enrico Attardi
AU - Guido A. Cavaletti
AU - Adriana C. Balduzzi
AU - Emma De Pater
AU - Andrea Biondi
AU - Angela M. Savino
AU - Jolanda Sarno
AU - Sarah Tettamanti
AU - Francesco Saettini
PY - 2026
DA - 2026/11/04
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1960580
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960580
AB - BackgroundGermline 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.MethodsWe 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.ResultsGATA2-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.ConclusionsGATA2 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.
SN - 1664-3224
ER -