title: CD27low natural killer cells prolong allograft survival in mice by controlling alloreactive CD8+ T cells in a T-bet-dependent manner.
abstract: BACKGROUND
  Natural killer (NK) cells play a dichotomous role in alloimmune responses because they are known to promote both allograft survival and rejection. The aim of this study was to investigate the role of functionally distinct NK cell subsets in alloimmunity with the hypothesis that this dichotomy is explained by the functional heterogeneity of distinct NK cell subsets.
  
  
  METHODS
  Because T-bet controls thematuration of NK cells from CD27high to terminally differentiated CD27low NK cells, we used Rag−/−T-bet−/− mice that lackmature CD27low NK cells to study the distinct roles of CD27low versus CD27high NK cells in a model of Tcell–mediated skin transplant rejection under costimulatory blockade conditions.
  
  
  RESULTS
  We found that T cell–reconstituted Rag1−/− recipients (possessing CD27low NK cells) show significantly prolonged allograft survival on costimulatory blockade when compared to Rag1−/−T-bet−/− mice (lacking CD27low NK cells), indicating that CD27low but not CD27high NK cells enhance allograft survival. Critically, Rag1−/−T-bet−/− recipients showed strikingly increased alloreactive memory CD8+ Tcell responses, as indicated by increased CD8+ Tcell proliferation and interferon-γ production. Therefore, we speculated that CD27low NK cells directly regulate alloreactive CD8+ Tcell responses under costimulatory blockade conditions. To test this, we adoptively transferred CD27low NK cells into Rag1−/−T-bet−/− skin transplant recipients and found that the CD27low NK cells restore better allograft survival by inhibiting the proliferation of alloreactive interferon-γ+CD8+ T cells.
  
  
  CONCLUSIONS
  In summary, mature CD27low NK cells promote allograft survival under costimulatory blockade conditions by regulating alloreactive memory CD8+ T-cell responses.
authors.affiliation: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors.forename: Margareta
authors.initials: M
authors.lastname: Lantow
authors.forename: Elke
authors.initials: E
authors.lastname: Eggenhofer
authors.forename: Manije
authors.initials: M
authors.lastname: Sabet-Baktach
authors.forename: Philipp
authors.initials: P
authors.lastname: Renner
authors.forename: Jordi
authors.initials: J
authors.lastname: Rovira
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Koehl
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Alexander
authors.initials: A
authors.lastname: Kroemer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D008213:Lymphocyte Activation; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D016038:Skin Transplantation / Q000009:adverse effects*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000172:deficiency* / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C064658:RAG-1 protein; D007371:Interferon-gamma