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 CD34(+)DNAM-1(bright)CXCR4(+) 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, Lin-CD34(+)DNAM-1(bright)CXCR4(+) precursors from patients with chronic infection, rapidly differentiate into cytotoxic, IFNy-secreting CD94/NKG2C(+)KIR(+)CD57(+) NK-cell progenies. An additional novel subset of common lymphocyte precursors was identified among Lin-CD34(-)CD56(-)CD16(+) cells and characterized by expression of CXCR4 and lack of perforM and CD94. Line(-)CD34(-)CD56(-)CD16(+)Perf(-)CD94(-)CXCR4(+) precursors are also endowed with generation potential toward memory-like NKG2C(+)NK 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.