Circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration
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.
Authors
- Karsten Hokamp (ORCID: https://orcid.org/0000-0001-7464-2370)
- Rachel Dalton (ORCID: https://orcid.org/0000-0001-8902-1155)
- Rose Anne Kenny (ORCID: https://orcid.org/0000-0002-9336-8124)
- Erin Fahey (ORCID: https://orcid.org/0000-0002-8871-2090)
- Kieva Byrne
- Natalie Hudson (ORCID: https://orcid.org/0000-0001-9163-8779)
- Matthew O'Riordan (ORCID: https://orcid.org/0000-0002-1268-7423)
- Kelly Mulfaul (ORCID: https://orcid.org/0000-0003-4441-4806)
- Luke Gibbons (ORCID: https://orcid.org/0000-0002-5724-0895)
- Kiva Brennan (ORCID: https://orcid.org/0000-0003-4960-7076)
- Matt McElheron (ORCID: https://orcid.org/0000-0003-2980-665X)
- Ema Ozaki
- Aline Zoller
- Nollaig Bourke
- Dara O’Boyle
- Mark T. Cahill
- Fiona Roche
- Derrick Feenstra
- Sarah Palko
- David Finlay
- Katie Robb
- Said Aktas
- Matthew Campbell
- Emma Connolly
- Sarah L. Doyle (ORCID: https://orcid.org/0000-0002-6294-9380)
- Eleanor Noone
- Robert F. Mullins
- Kieran P. Byrne
Institutions
- Mercer (Czechia) (CZ)
- Roche (Switzerland) (CH)
- University of Iowa (US)
- Trinity College Dublin (IE)
- Progress (Ireland) (IE)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2026-05-01
- DOI
- https://doi.org/10.1016/j.xcrm.2026.102792
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Roche
- BrightFocus Foundation
- Health Research Board
- Science Foundation Ireland
- Irish Research Council
- European Research Council