Project information

The study of natural killer cells in AT pathogenesis and their therapeutic implications

Principal researchers: Dr Margherita Doria (right) and Dr. Maria Giovanna Desimio
Institute: Bambino Gesù Children’s Hospital, Rome, Italy
Cost: £91,000 over 24 months in partnership with Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)
Completed: 31st December 2025

Project Overview
This project set out to understand how natural killer (NK) cells, a key part of the immune system’s defence against viruses and cancer, function in people with AT. Earlier work suggested that NK cells in AT may be impaired because of changes in a receptor called NKG2D, which helps NK cells recognise and destroy abnormal cells. By studying both AT patients and an ATM deficient mouse model, the team aimed to identify biomarkers of disease progression and explore potential therapeutic strategies that could strengthen immune responses in AT.

Research Methods and Outcome
The team used blood samples from 31 people with AT recruited across four Italian hospitals to study how their natural killer (NK) cells function. Peripheral blood mononuclear cells (PBMCs) were isolated and analysed using flow cytometry to assess NK cell subsets, receptor expression, and markers of activation or exhaustion. Functional assays measured the ability of NK cells to kill tumour targets and to produce IFN γ after stimulation. Plasma from the same samples was tested for 17 cytokines and several soluble NKG2D ligands using multiplex Luminex and ELISA. PBMCs were used to analyse the phenotype and function of natural killer (NK) cells and the levels of several factors that modulate immunity were measured in plasma samples. Parallel experiments in ATM deficient mice helped clarify whether the defects seen in patients were directly linked to loss of ATM.

The study found that although NK cell numbers were preserved and their function was significantly impaired. AT NK cells showed reduced expression of the activating receptor NKG2D, increased expression of the inhibitory receptor PD 1, and a marked reduction in both tumour killing capacity and cytokine production. Plasma from AT patients contained high levels of inflammatory and immunosuppressive molecules, including IL 6 and TGF β, with strong correlations between these factors and NK cell dysfunction. The team also established that NK cells of AT patients displayed impaired effector functions and that TGF β accumulation in AT plasma was observed for the first time. These findings suggest that chronic inflammation and soluble NKG2D ligands contribute to NK cell exhaustion.
Importantly, the team also explored potential therapeutic strategies. When patient cells were exposed to IL 15, NK cell receptor expression improved and cytotoxic function was partially restored, even in the presence of TGF β. This indicates that NK cell based immunotherapies—already advancing in cancer treatment—may be adaptable for AT. Overall, the study provides a detailed map of NK cell abnormalities in AT and identifies several promising biomarkers and intervention points that could support future clinical advances.

What next?
The team plan to focus on making the most of the rich dataset they have collected and will begin to translate their findings into future treatment possibilities. They are now applying advanced statistical methods to explore how the immune changes they observed—such as high levels of IL 6, TGF β and soluble NKG2D ligands—relate to real world outcomes like recurrent infections, cancer risk and immune deficiency. This deeper analysis aims to identify reliable biomarkers that could help clinicians track disease progression or tailor care more effectively.
Alongside this, the team will build on their encouraging laboratory results showing that IL 15 can restore NK cell function, even in the presence of strong immunosuppressive signals. This opens the door to exploring NK cell based immunotherapies, which are already being tested in cancer treatment, as potential future options for people with AT who cannot tolerate standard chemotherapy or radiotherapy.
They are also preparing additional scientific publications to share their findings with the wider research community and support future collaborations.