Margherita Doria, Italy
Bambino Gesù Children's Hospital University Department of PediatricsPresenter of 1 Presentation
ALTERED NATURAL KILLER CELLS IN ATAXIA-TELANGIECTASIA PATIENTS
Abstract
Background and Aims
Ataxia-telangiectasia (AT) is a neurodegenerative disorder caused by mutations in the gene encoding the ATM kinase, a key regulator of the DNA damage response (DDR) pathway. Susceptibility to cancer and pulmonary infections dramatically reduce life expectancy. Over 60% of AT patients show variable immunodeficiency, with progressive B- and T-cell lymphopenia and abnormal immunoglobulin levels. Here we studied the NK cell compartment of AT patients, with a special focus on the NKG2D activating receptor that potently triggers cytotoxicity upon engagement by ligands (NKG2DL) induced via the DDR pathway on infected or transformed cells.
Methods
In four patients (AT#1-4), NK cell phenotype and function and NKG2DL expression on various cell types were analyzed by flow cytometry. Plasma soluble NKG2DLs (sNKG2DLs) were measured by ELISA. NKG2D expression was evaluated by western blotting and qRT-PCR in NK cells of AT#1-2 patients.
Results
NK cells had normal frequencies but were skewed towards the CD56neg anergic subset in AT#1-2, with AT#2 also showing impaired NK-cell cytotoxicity. All patients showed down-regulation of at least one NK-cell activating receptor (NKG2D, NKp46, DNAM-1). When analyzed, NKG2D was reduced at the protein but not at the mRNA level and resulted in lower NKG2D-mediated cytotoxicity. In all patients, both basal and induced expression of NKG2Ls was increased on B and T lymphocytes and at least one sNKG2DL accumulated in AT plasma.
Conclusions
NK cells are disturbed in AT patients. Alteration of the NKG2D/NKG2DL axis found herein may contribute to infection susceptibility and development of lymphoproliferative disorders or malignancies.