title: Generation of a novel regulatory NK cell subset from peripheral blood CD34+ progenitors promoted by membrane-bound IL-15.
abstract: BACKGROUND
  NK cells have been long time considered as cytotoxic lymphocytes competent in killing virus-infected cells and tumors. However, NK cells may also play essential immuno-regulatory functions. In this context, the real existence of a defined NK subset with negative regulatory properties has been hypothesized but never clearly demonstrated.
  
  
  RESULTS
  Herein, we show the in vitro generation from human peripheral blood haematopoietic progenitors (PB-HP), of a novel subset of non-cytolytic NK cells displaying a mature phenotype and remarkable immuno-regulatory functions (NK-ireg). The main functional hallmark of these NK-ireg cells is represented by the surface expression/release of HLA-G, a major immunosuppressive molecule. In addition, NK-ireg cells secrete two powerful immuno-regulatory factors: IL-10 and IL-21. Through these factors, NK-ireg cells act as effectors of the down-regulation of the immune response: reconverting mature myeloid DC (mDC) into immature/tolerogenic DC, blocking cytolytic functions on conventional NK cells and inducing HLA-G membrane expression on PB-derived monocytes. The generation of "NK-ireg" cells is obtained, by default, in culture conditions favouring cell-to-cell contacts, and it is strictly dependent on reciprocal trans-presentation of membrane-bound IL-15 forms constitutively and selectively expressed by human CD34(+) PB-HP. Finally, a small subset of NKp46(+) HLA-G(+) IL-10(+) is detected within freshly isolated decidual NK cells, suggesting that these cells could represent an in vivo counterpart of the NK-ireg cells.
  
  
  CONCLUSIONS
  In conclusion, NK-ireg cells represent a novel truly differentiated non-cytolytic NK subset with a self-sustainable phenotype (CD56(+) CD16(+) NKp30(+) NKp44(+) NKp46(+) CD94(+) CD69(+) CCR7(+)) generated from specific pSTAT6(+) GATA3(+) precursors. NK-ireg cells could be employed to develop new immuno-suppressive strategies in autoimmune diseases, transplant rejection or graft versus host diseases. In addition, NK-ireg cells can be easily derived from peripheral blood of the patients and could constitute an autologous biotherapic tool to be used combined or in alternative to other immuno-regulatory cells.
authors.affiliation: INSERM, UMR 542, Université de Paris XI, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Massimo
authors.initials: M
authors.lastname: Giuliani
authors.forename: Julien
authors.initials: J
authors.lastname: Giron-Michel
authors.forename: Simone
authors.initials: S
authors.lastname: Negrini
authors.forename: Paola
authors.initials: P
authors.lastname: Vacca
authors.forename: Deniz
authors.initials: D
authors.lastname: Durali
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Bousse-Kerdiles
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Aurore
authors.initials: A
authors.lastname: Devocelle
authors.forename: Rajia
authors.initials: R
authors.lastname: Bahri
authors.forename: Antoine
authors.initials: A
authors.lastname: Durrbach
authors.forename: Yassine
authors.initials: Y
authors.lastname: Taoufik
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Michela
authors.initials: M
authors.lastname: Croce
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Bruno
authors.initials: B
authors.lastname: Azzarone
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology*; D007694:Killer Cells, Natural / Q000145:classification*; D016131:Lymphocyte Subsets; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology
chemical_list: D018952:Antigens, CD34; D019409:Interleukin-15