Acquired Senescent T-Cell Phenotype Correlates with Clinical Severity in GATA Binding Protein 2-Deficient Patients

Abstract

GATA binding protein 2 (GATA2) deficiency is a rare disorder of hematopoiesis, lymphatics, and immunity caused by spontaneous or autosomal dominant mutations in the GATA2 gene. Clinical manifestations range from neutropenia, lymphedema, deafness, to severe viral and mycobacterial infections, bone marrow failure, and acute myeloid leukemia. Patients also present with monocytopenia, dendritic cell, B- and natural killer (NK)-cell deficiency. We studied the T-cell and NK-cell compartments of four GATA2-deficient patients to assess if changes in these lymphocyte populations could be correlated with clinical phenotype. Patients with more severe clinical complications demonstrated a senescent T-cell phenotype whereas patients with lower clinical score had undetectable changes relative to controls. In contrast, patients’ NK-cells demonstrated an immature/activated phenotype that did not correlate with clinical score, suggesting an intrinsic NK-cell defect. These studies will help us to determine the contribution of T- and NK-cell dysregulation to the clinical phenotype of GATA2 patients, and may help to establish the most accurate therapeutic options for these patients. Asymptomatic patients may be taken into consideration for hematopoietic stem cell transplantation when dysregulation of T-cell and NK-cell compartment is present.

Infectious Complications Predict Premature CD8+ T-cell Senescence in CD40 Ligand-Deficient Patients

“…GATA binding protein 2 (GATA2) deficiency is a rare disorder that has clinical manifestations of bone marrow failure, acute myeloid leukemia, deafness, severe viral, and bacterial infections. In a small number of GATA2-deficient patients with history of severe infections, the expansion of memory CD8 + T-cells was reported [40]. These findings, together with the results of our study, support that CD8 + T-cell senescence can occur in patients with PIDs, especially those who have suffered from significant infections.…”

Germline GATA2 Mutation and Bone Marrow Failure

“…The remaining NK cells have decreased CXCL12/CXCR4-dependent chemotaxis, while the B cells have increased CXCL12-induced chemotaxis 48 . Ruiz-Garcia studied four patients and showed that those with worse clinical phenotype had increased T cell senescence 49 .…”

The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID)

“…GATA2 deficient patients showed severe immunological features in parallel with senescent T cell phenotype and B cell lymphopenia. This gene is also reported more frequently in CVID pre-diagnosed patients in Mediterranean region populations 27 , 28 .…”