Generation of a novel regulatory NK cell subset from peripheral blood CD34+ progenitors promoted by membrane-bound IL-15
Authors: Michela Croce
Yassine Taoufik
Anne Caignard
Julien Giron-Michel
Deniz Durali
Salem Chouaib
Silvano Ferrini
Aurore Devocelle
Paola Vacca
Antoine Durrbach
Maria Cristina Mingari
Simone Negrini
Bruno Azzarone
Rajia Bahri
Lorenzo Moretta
Massimo Giuliani
Caroline Le Bousse-Kerdiles
Journal: PLoS ONE (2008)
Discipline: Multidisciplinary
Keywords: NK cells; immuno-regulatory functions; HLA-G; IL-10; IL-21
Affiliations: INSERM, UMR 542, Universit√© de Paris XI, H√¥pital Paul Brousse, Villejuif, France.

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 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/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. 

Retracted: No

PubPeer comments:
 An Expression of Concern was published by the authors of  The personality types of key catalytic individuals shape colonies collective behaviour and success (published in Animal Behavior; 2014). https: doi.org 10.1016 j.anbehav.2021.01.010 For transparency, I have now uploaded a second excel file onto my figshare page which highlights the duplicated sequences described in this Expression of Concern: https: figshare.com articles dataset Data_for_Pruitt_and_Keiser_2014_-_Animal_Behaviour_xlsx 11786505. Duplicated sequences are denoted with via highlighting with same color. For context, this experiment was conducted collaboratively by members of the Pruitt Lab at the University of Pittsburgh in 2014. The boldness assays on individual spiders were conducted by myself and the undergraduates listed in our acknowledgements section. As I recall, the boldness data were recorded into shared lab notebooks and entered into excel sheets on a shared lab computer. We then used a random number generator to place individuals into each experimental colony. As I recall, the collective behavior assays were conducted by Pruitt and myself. These data were recorded in shared lab notebooks and entered into excel spreadsheets on a shared lab computer. I do not have access to any of the original notebooks, as they remained in the Pruitt Lab. The data were analyzed by Pruitt, but one of my tasks was to create the figures, so I was given excel sheets to do so. It wasn t until 2020 that the repeated sequences were brought to our attention. As noted in the expression of concern:  Further consideration will be given once original notebooks are provided for cross-referencing. ,