Generation of a novel regulatory NK cell subset from peripheral blood CD34+ progenitors promoted by membrane-bound IL-15

Massimo Giuliani, Julien Giron-Michel, Simone Negrini, Paola Vacca, Deniz Durali, Anne Caignard, Caroline Le Bousse-Kerdiles, Salem Chouaib, Aurore Devocelle, Rajia Bahri, Antoine Durrbach, Yassine Taoufik, Silvano Ferrini, Michela Croce, Maria Cristina Mingari, Lorenzo Moretta, Bruno Azzarone

Research output: Contribution to journalArticlepeer-review

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. Methodology/Principal Findings: 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 immunosuppresive 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 including 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/Significance: 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.

Original languageEnglish
Article numbere2241
JournalPLoS One
Volume3
Issue number5
DOIs
Publication statusPublished - May 21 2008

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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