Altered NK-cell compartment and dysfunctional NKG2D/NKG2D-ligand axis in patients with ataxia-telangiectasia

Maria Giovanna Desimio, Andrea Finocchi, Gigliola Di Matteo, Silvia Di Cesare, Carmela Giancotta, Francesca Conti, Luciana Chessa, Maria Piane, Davide Montin, Marta Dellepiane, Paolo Rossi, Caterina Cancrini, Margherita Doria

Research output: Contribution to journalArticlepeer-review


Ataxia-telangiectasia (A-T) is a multisystem disorder caused by biallelic pathogenic variants in the gene encoding A-T mutated (ATM) kinase, a master regulator of the DNA damage response (DDR) pathway. Most A-T patients show cellular and/or humoral immunodeficiency that has been associated with cancer risk and reduced survival, but NK cells have not been thoroughly studied. Here we investigated NK cells of A-T patients with a special focus on the NKG2D receptor that triggers cytotoxicity upon engagement by its ligands (NKG2DLs) commonly induced via the DDR pathway on infected, transformed, and variously stressed cells. Using flow cytometry, we examined the phenotype and function of NK cells in 6 A-T patients as compared with healthy individuals. NKG2D expression was evaluated also by western blotting and RT-qPCR; plasma soluble NKG2DLs (sMICA, sMICB, sULBP1, ULBP2) were measured by ELISA. Results showed that A-T NK cells were skewed towards the CD56neg anergic phenotype and displayed decreased expression of NKG2D and perforin. NKG2D was reduced at the protein but not at the mRNA level and resulted in impaired NKG2D-mediated cytotoxicity in 4/6 A-T patients. Moreover, in A-T plasma we found 24-fold and 2-fold increase of sMICA and sULBP1, respectively, both inversely correlated with NKG2D expression. Overall, NK cells are disturbed in A-T patients showing reduced NKG2D expression, possibly caused by persistent engagement of its ligands, that may contribute to susceptibility to cancer and infections and represent novel targets for therapeutic interventions.

Original languageEnglish
Pages (from-to)108802
JournalClin. Immunol.
Publication statusPublished - Sept 2021


  • Adolescent
  • Ataxia Telangiectasia/genetics
  • Case-Control Studies
  • Cell Line
  • Child
  • Cytotoxicity, Immunologic
  • Down-Regulation
  • Female
  • Flow Cytometry
  • GPI-Linked Proteins/blood
  • Histocompatibility Antigens Class I/blood
  • Humans
  • Intercellular Signaling Peptides and Proteins/blood
  • Intracellular Signaling Peptides and Proteins/blood
  • K562 Cells
  • Killer Cells, Natural/immunology
  • Ligands
  • Male
  • NK Cell Lectin-Like Receptor Subfamily K/genetics
  • Phenotype
  • RNA, Messenger/genetics
  • Young Adult


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