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Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG)
Roberto García-López1, María Eugenia de la Morena-Barrio2,3, Laia Alsina4
1Departamento de Bioquímica, Biología Molecular B e Inmunología, Facultad de Medicina, IMIB-University of Murcia, Murcia, Spain.
Background:
PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.
Objective:
To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors.
Methods:
We studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay.
Results:
We found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules.
Conclusions:
Our results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves our understanding of the immunological functions in PMM2-CDG and possibly in other CDG-I types.
Insights
Natural killer (NK) cells in PMM2-CDG patients show altered reactivity and receptor expression, impacting anti-viral immunity. This study reveals potential defects in NK cell killing activity and immune response control in PMM2-CDG.
Area of Science:
- Immunology
- Glycoscience
- Human Genetics
Background:
- PMM2-CDG is the most common N-glycosylation disorder, associated with severe early-life infections.
- Natural killer (NK) cells are crucial for immunity against pathogens and regulating adaptive immunity.
- The impact of PMM2-CDG on NK cell function remains largely unexplored.
Purpose of the Study:
- To investigate potential defects in NK cell number, killing activity, and receptor expression in PMM2-CDG patients.
- To evaluate the functional consequences of PMM2-CDG on NK cell-mediated immune responses.
- To enhance understanding of immunological dysfunction in PMM2-CDG.
Main Methods:
- Flow cytometry was used to analyze NK cell numbers and surface receptor expression.
- NK cell killing activity and responsiveness were assessed using NK cytotoxicity assays against K562 target cells.
- Fresh and activated NK cells from twelve PMM2-CDG patients were studied.
Main Results:
- Increased blood NK cell counts were observed in patients with severe PMM2-CDG phenotypes.
- Activated NK cells from PMM2-CDG patients exhibited increased expression of CD54, NKG2D, and NKp46.
- NK cell responsiveness was higher in PMM2-CDG patients, with increased cytolytic activity correlated to CD54 and NKG2D expression.
Conclusions:
- Hypoglycosylation in PMM2-CDG alters NK cell reactivity and the expression of key activating receptors (CD54, NKG2D, NKp46, 2B4).
- These findings suggest a defective control of NK cell killing activity and anti-viral immunity in PMM2-CDG.
- This research advances the understanding of immunological functions in PMM2-CDG and other CDG-I types.
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