title: Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation.
abstract: In contrast to other solid organ transplantations, liver grafts have tolerogenic properties. Animal models indicate that donor leukocytes transferred into the recipient after liver transplantation (LTX) play a relevant role in this tolerogenic phenomenon. However, the specific donor cell types involved in modulation of the recipient alloresponse are not yet defined. We hypothesized that this unique property of liver grafts may be related to their high content of organ-specific natural killer (NK) and CD56(+) T cells. Here, we show that a high proportion of hepatic NK cells that detach from human liver grafts during pretransplant perfusion belong to the CD56bright subset, and are in an activated state (CD69(+)). Liver NK cells contained perforin and granzymes, exerted stronger cytotoxicity against K562 target cells when compared with blood NK cells, and secreted interferon-gamma, but no interleukin-10 or T helper 2 cytokines, upon stimulation with monokines. Interestingly, whereas the CD56bright subset is classically considered as noncytolytic, liver CD56bright NK cells showed a high content of cytolytic molecules and degranulated in response to K562 cells. After LTX, but not after renal transplantation, significant numbers of donor CD56dim NK and CD56(+) T cells were detected in the recipient circulation for approximately 2 weeks. In conclusion, during clinical LTX, activated and highly cytotoxic NK cells of donor origin are transferred into the recipient, and a subset of them mixes with the recirculating recipient NK cell pool. The unique properties of the transferred hepatic NK cells may enable them to play a role in regulating the immunological response of the recipient against the graft and therefore contribute to liver tolerogenicity.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Viviana
authors.initials: V
authors.lastname: Moroso
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Shanta
authors.initials: S
authors.lastname: Mancham
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.forename: Diana
authors.initials: D
authors.lastname: Eissens
authors.forename: Arnold
authors.initials: A
authors.lastname: van der Meer
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D019002:CD56 Antigen / Q000378:metabolism; D002465:Cell Movement; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019041:L-Selectin / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology*; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014180:Transplantation
chemical_list: D019002:CD56 Antigen; D016023:Integrins; C071777:integrin alpha4beta7; D019041:L-Selectin; D007371:Interferon-gamma