HCMV-controlling NKG2C NK cells originate from novel circulating inflammatory precursors.

BACKGROUND

There is limited knowledge on the origin and development from CD34 precursors of the ample spectrum of human natural killer (NK) cells, particularly of specialized NK subsets.

OBJECTIVE

This study sought to characterize the NK-cell progeny of CD34DNAM-1CXCR4 and of other precursors circulating in the peripheral blood of patients with chronic viral infections (eg, HIV, hepatitis C virus, cytomegalovirus reactivation).

METHODS

Highly purified precursors were obtained by flow cytometric sorting and cultured in standard NK-cell differentiation media (ie, SCF, FLT3, IL-7, IL-15). Phenotypic and functional analyses on progenies were performed by multiparametric cytofluorimetric assays. Transcriptional signatures of NK-cell progenies were studied by microarray analysis. Inhibition of cytomegalovirus replication was studied by PCR.

RESULTS

Unlike conventional CD34 precursors, LinCD34DNAM-1CXCR4 precursors from patients with chronic infection, rapidly differentiate into cytotoxic, IFN-γ-secreting CD94/NKG2CKIRCD57 NK-cell progenies. An additional novel subset of common lymphocyte precursors was identified among LinCD34CD56CD16 cells and characterized by expression of CXCR4 and lack of perforin and CD94. LinCD34CD56CD16PerfCD94CXCR4 precursors are also endowed with generation potential toward memory-like NKG2CNK cells. Maturing NK-cell progenies mediated strong human cytomegalovirus-inhibiting activity. Microarray analysis confirmed a transcriptional signature compatible with NK-cell progenies and with maturing adaptive NK cells.

CONCLUSIONS

During viral infections, precursors of adaptive NK cells are released and circulate in the peripheral blood.