Transient tissue residency and lymphatic egress define human CD56bright NK cell homeostasis
Human tissue-resident (TR) CD56<sup>bright</sup> natural killer (NK) cells can be identified by expression of integrins and chemokine receptors inferred from murine studies, but many aspects of their homeostasis are unclear. Here we used an integrated approach of dynamic human, humanized mouse and non-human primate models and sampling of efferent lymph fluid to determine recirculation and TR patterns of human NK cells. By intravascular labeling, we showed that CD56<sup>bright</sup> NK cells access tissue niches at steady state. Furthermore, in human liver transplantation, donor-derived CD56<sup>bright</sup> NK cells represent the dominant TR NK cell population early after transplantation, but are replaced over time by infiltrating recipient NK cells that establish TR traits, a process partly regulated by Runx3. Transient TR CD56<sup>bright</sup> NK cells recirculated via lymphatics, displaying a consistent phenotype detectable in draining lymph nodes and efferent lymph fluid, and waned from peripheral blood on lymph node egress blockade. Finally, CD56<sup>dim</sup> NK cells, constrained to vasculature at steady state, entered lymph nodes upon inflammation. This study provides a mechanistic framework for the transient tissue residency and recirculation pattern of human NK cell populations.
Authors
- Julia Hengst (ORCID: https://orcid.org/0000-0001-5873-9068)
- George Tweet (ORCID: https://orcid.org/0009-0004-7811-1744)
- Iva Filipovic (ORCID: https://orcid.org/0000-0002-8166-5500)
- Bo‐Göran Ericzon (ORCID: https://orcid.org/0000-0001-5604-2427)
- Son Nguyen (ORCID: https://orcid.org/0000-0002-0475-5158)
- Luisa Klotz (ORCID: https://orcid.org/0000-0001-5439-9633)
- Dan Sun (ORCID: https://orcid.org/0000-0003-2147-9308)
- Michael R. Betts (ORCID: https://orcid.org/0000-0002-7690-1484)
- Niklas K. Björkström (ORCID: https://orcid.org/0000-0002-0967-076X)
- Natalie Sleiers
- Carl Jorns (ORCID: https://orcid.org/0000-0001-7727-8113)
- Gregory J. Golden (ORCID: https://orcid.org/0000-0002-4063-7116)
- Itzel Medina-Andrade (ORCID: https://orcid.org/0009-0001-1625-4887)
- Vera Nilsén
- Martin Cornillet (ORCID: https://orcid.org/0000-0001-7981-0927)
- Ernesto Sparrelid (ORCID: https://orcid.org/0000-0003-0259-8328)
- James J. Knox (ORCID: https://orcid.org/0000-0002-3523-0661)
- Otto Strauß
- Tim Willinger (ORCID: https://orcid.org/0000-0002-8720-7199)
- Yu Gao (ORCID: https://orcid.org/0000-0002-4615-3614)
- Annika Niehrs (ORCID: https://orcid.org/0000-0002-2190-4346)
- Yongna Xing (ORCID: https://orcid.org/0000-0002-9834-528X)
- Martin A. Ivarsson (ORCID: https://orcid.org/0000-0002-7745-1331)
- Andrea Ponzetta (ORCID: https://orcid.org/0000-0003-3224-802X)
- Marcus Buggert (ORCID: https://orcid.org/0000-0003-0633-1719)
- Maxim Itkin (ORCID: https://orcid.org/0000-0003-1361-7109)
- Benedikt Strunz (ORCID: https://orcid.org/0000-0001-9974-6133)
- Mirko Paiardini (ORCID: https://orcid.org/0000-0002-7276-3600)
- Murat Kürtüncü (ORCID: https://orcid.org/0000-0003-3286-2652)
- Inger Nordström
- Vincent H. Wu (ORCID: https://orcid.org/0000-0002-8640-6065)
- Greg Nowak (ORCID: https://orcid.org/0000-0001-8766-8860)
- M. Betina Pampena (ORCID: https://orcid.org/0000-0001-6665-4865)
- Yoav Dori (ORCID: https://orcid.org/0000-0003-0531-8723)
- Christoph Ziegenhain (ORCID: https://orcid.org/0000-0003-2208-4877)
- Claudia Janoschka (ORCID: https://orcid.org/0000-0003-0947-1805)
- Heiner H. Wedemeyer (ORCID: https://orcid.org/0000-0003-2906-0480)
- Christopher Maucourant (ORCID: https://orcid.org/0000-0003-1033-2992)
- Maura Statzu (ORCID: https://orcid.org/0000-0003-0070-2195)
- R. Keith Reeves (ORCID: https://orcid.org/0000-0003-3157-2557)
- Kyle Kroll (ORCID: https://orcid.org/0000-0002-9237-9497)
- A Alisjahbana (ORCID: https://orcid.org/0000-0002-8400-8039)
- Laura Hertwig (ORCID: https://orcid.org/0000-0002-1170-0948)
- Marie Schaffer
- Sadia Samer
Institutions
- Beth Israel Deaconess Medical Center (US)
- Karolinska University Hospital (SE)
- Children's Hospital of Philadelphia (US)
- Bowdoin College (US)
- Emory University (US)
- Duke University (US)
- Hong Kong University of Science and Technology (HK)
- Columbia University Irving Medical Center (US)
- Hospital of the University of Pennsylvania (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Karolinska Institutet (SE)
- Medizinische Hochschule Hannover (DE)
- University Hospital Münster (DE)
- Essen University Hospital (DE)
- Center for Genomic Science (IT)
- Istanbul University (TR)
- Columbia University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1038/s41590-025-02290-9
- Citations
- 3
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- Yale University
- Children's Hospital of Philadelphia
- University of Pennsylvania
- Emory University
- Regeneron Pharmaceuticals
- European Commission
- Stiftelsen för Strategisk Forskning
- Cancerfonden
- Svenska Sällskapet för Medicinsk Forskning
- Hjärt-Lungfonden
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Stockholms Läns Landsting
- Vetenskapsrådet
- Medizinischen Hochschule Hannover
- Novo Nordisk Fonden
- National Institutes of Health
- Uppsala Multidisciplinary Center for Advanced Computational Science
- Center for Innovative Medicine
- National Institute of Allergy and Infectious Diseases