Circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration

Kiva Brennan; Ema Ozaki; Eleanor Noone; Sarah Palko; Kieran P Byrne; Fiona Roche; Matt McElheron; Kieva Byrne; Luke Gibbons; Katie Robb; Said Aktas; Emma Connolly; Natalie Hudson; Matthew M O'Riordan; Dara O'Boyle; Rachel Dalton; Aline Zoller; Erin Fahey; Karsten Hokamp; Derrick Feenstra; Nollaig Bourke; Matthew Campbell; David Finlay; Kelly Mulfaul; Robert F Mullins; Rose Anne Kenny; Mark T Cahill; Sarah L Doyle

doi:10.1016/j.xcrm.2026.102792

Back

Circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration

Journal article

Open access

Peer reviewed

Circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration

Kiva Brennan, Ema Ozaki, Eleanor Noone, Sarah Palko, Kieran P Byrne, Fiona Roche, Matt McElheron, Kieva Byrne, Luke Gibbons, Katie Robb, …

Cell reports. Medicine, Vol.7(6), 102792

06/12/2026

DOI: 10.1016/j.xcrm.2026.102792

PMCID: PMC13293971

PMID: 42102824

Files and links (1)

url

https://doi.org/10.1016/j.xcrm.2026.102792View

Published (Version of record) Open Access

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible central blindness and can result in pathological neovascularization. Using a "human-first" approach, we identify immunotherapy as a disease modifier in models of neovascular AMD (nAMD). Plasma cytokine analysis in a large population cohort reveals an imbalance of lymphocytic cytokines associated with severity of AMD, leading to discovery of a skewed peripheral natural killer (NK) cell phenotype in individuals with AMD. Peripheral NK cells are rapidly activated in nAMD models, and single-cell RNA sequencing demonstrates expansion of activated cytolytic NK cells within neovascular lesions during resolution. NK cells localize to neovessels in human AMD donor eyes; however, they exhibit markers of terminal differentiation and quiescence. Adoptive transfer of pre-activated NK cells reduces neovascularization and restores barrier integrity. Our data identify a distinct, functionally altered NK cell phenotype in nAMD and suggests harnessing NK cells represents an immunotherapeutic alternative for the treatment of nAMD.

Immunotherapy

natural killer cells

neovascular

choroidal neovascularization

age-related macular degeneration

IL-18

Details

Title: Subtitle: Circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration
Creators: Kiva Brennan - Trinity College Dublin
Ema Ozaki - Trinity College Dublin
Eleanor Noone - Trinity College Dublin
Sarah Palko - Trinity College Dublin
Kieran P Byrne - Trinity College Dublin
Fiona Roche - Trinity College Dublin
Matt McElheron - Trinity College Dublin
Kieva Byrne - Trinity College Dublin
Luke Gibbons - Trinity College Dublin
Katie Robb - Trinity College Dublin
Said Aktas - Roche (Switzerland)
Emma Connolly - Trinity College Dublin
Natalie Hudson - Trinity College Dublin
Matthew M O'Riordan - Trinity College Dublin
Dara O'Boyle
Rachel Dalton - Trinity College Dublin
Aline Zoller - Trinity College Dublin
Erin Fahey - Trinity College Dublin
Karsten Hokamp - Trinity College Dublin
Derrick Feenstra - Roche (Switzerland)
Nollaig Bourke - Trinity College Dublin
Matthew Campbell - Trinity College Dublin
David Finlay - Trinity College Dublin
Kelly Mulfaul - University of Iowa
Robert F Mullins - University of Iowa
Rose Anne Kenny - Mercer (Czechia)
Mark T Cahill - Progress (Ireland)
Sarah L Doyle - Trinity College Dublin
Resource Type: Journal article
Publication Details: Cell reports. Medicine, Vol.7(6), 102792
DOI: 10.1016/j.xcrm.2026.102792
PMID: 42102824
PMCID: PMC13293971
NLM abbreviation: Cell Rep Med
ISSN: 2666-3791
eISSN: 2666-3791
Publisher: Elsevier
Grant note: Science Foundation Ireland: SFI-15/CDA/3497, SFI-18/TIDA/6067, SFI/21SPP/3732 Irish Research Council: IRCLA/2017/295 Health Research Board (HRB) Ireland with Fighting Blindness: HRB/MRCG-2018-08 European Research Council (ERC NK InSight): 101087802 Royal Victoria Eye and Ear Hospital (RVEEH): HRB/MRCG-2018-08 F. Hoffmann-La Roche Immunology, Infectious Disease and Ophthalmology Incubator program, and BrightFocus Foundation NIH: EY-024605 Irish Government Department of Health: 101087802 Atlantic Philanthropies Irish Life: EY-024605, TILDA-2017-1 HRB: TILDA-2017-1, TILDA-2023-001
We wish to thank all participants who donated blood for this project, the donors and their families for the healthy and AMD eye tissue, and TILDA participants for their valuable contribution to the study. We would like to thank the TILDA research team, study nurses, and administrators. The authors wish to acknowledge technical assistance from Dr. Barry Moran, Dr. Alfonso Blanco, and Ms Alison Murphy. Experimental schematics were created in BioRender by S.L.D. (2025/2026).Supported by Science Foundation Ireland (SFI-15/CDA/3497 and SFI-18/TIDA/6067) to S.L.D.; Science Foundation Ireland (SFI/21SPP/3732) to S.L.D. and M.C.; Irish Research Council (IRCLA/2017/295) to S.L.D.; Health Research Board (HRB) Ireland with Fighting Blindness (HRB/MRCG-2018-08) to S.L.D.; European Research Council (ERC NK InSight-101087802) to S.L.D.; Royal Victoria Eye and Ear Hospital (RVEEH) to S.L.D. and M.T.C.; F. Hoffmann-La Roche Immunology, Infectious Disease and Ophthalmology Incubator program, and BrightFocus Foundation to K.M.; and NIH (EY-024605) to R.F.M. TILDA was supported by Irish Government Department of Health, Atlantic Philanthropies, Irish Life, and HRB awards (TILDA-2017-1 and TILDA-2023-001). Funders had no involvement in study design, collection, analysis and interpretation of data, or authorship of the submitted work.
Language: English
Electronic publication date: 05/07/2026
Date published: 06/12/2026
Academic Unit: The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Ophthalmology and Visual Sciences
Record Identifier: 9985163468702771

Metrics

7 Record Views