Generation of a novel regulatory NK cell subset from peripheral blood CD34+ progenitors promoted by membrane-bound IL-15.
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.
Giuliani
Massimo
M
INSERM, UMR 542, Université de Paris XI, Hôpital Paul Brousse, Villejuif, France.
Giron-Michel
Julien
J
Negrini
Simone
S
Vacca
Paola
P
Durali
Deniz
D
Caignard
Anne
A
Le Bousse-Kerdiles
Caroline
C
Chouaib
Salem
S
Devocelle
Aurore
A
Bahri
Rajia
R
Durrbach
Antoine
A
Taoufik
Yassine
Y
Ferrini
Silvano
S
Croce
Michela
M
Mingari
Maria Cristina
MC
Moretta
Lorenzo
L
Azzarone
Bruno
B
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
D018952:Antigens, CD34; D019409:Interleukin-15