High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction
Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.
Authors
- Miguel Fribourg (ORCID: https://orcid.org/0000-0003-1804-8136)
- Amir Horowitz (ORCID: https://orcid.org/0000-0003-3100-2810)
- Paolo Cravedi (ORCID: https://orcid.org/0000-0001-7837-0923)
- Maureen P. Martin (ORCID: https://orcid.org/0000-0002-0990-3500)
- Mary Carrington (ORCID: https://orcid.org/0000-0002-2692-2180)
- Ronaldo M. de Real
- Daniel Geanon (ORCID: https://orcid.org/0009-0002-8331-7996)
- Yeon-Hwa Park
- Nicholas Chun (ORCID: https://orcid.org/0000-0001-6884-3686)
- Seunghee Kim‐Schulze (ORCID: https://orcid.org/0000-0003-0192-4400)
- Yuko Yuki (ORCID: https://orcid.org/0000-0003-1721-6003)
- Geoffrey C. Kelly (ORCID: https://orcid.org/0000-0002-3490-8514)
- Dan Fu Ruan (ORCID: https://orcid.org/0000-0003-4598-0199)
- Peter S. Heeger (ORCID: https://orcid.org/0000-0003-4673-6913)
- Rachel Lee (ORCID: https://orcid.org/0009-0009-5024-0647)
- Brian Lee (ORCID: https://orcid.org/0000-0002-3592-8146)
- Haocheng Yu
Institutions
- Cedars-Sinai Medical Center (US)
- Cancer Institute (WIA) (IN)
- Ragon Institute of MGH, MIT and Harvard (US)
- Tisch Hospital (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Precision Research (United States) (US)
- Tisch Cancer Institute
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1172/jci.insight.185687
- Citations
- 5
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.20
Funders
- U.S. Department of Health and Human Services
- Frederick National Laboratory for Cancer Research
- National Institutes of Health