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-1brightCXCR4+ 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-1brightCXCR4+ precursors from patients with chronic infection, rapidly differentiate into cytotoxic, IFN-γ-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 perforin and CD94. Lin-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.
['Bozzano|Federica|F|', 'Della Chiesa|Mariella|M|', 'Pelosi|Andrea|A|', 'Antonini|Francesca|F|', 'Ascierto|Maria Libera|ML|', 'Del Zotto|Genny|G|', 'Moretta|Francesca|F|', 'Muccio|Letizia|L|', 'Luganini|Anna|A|', 'Gribaudo|Giorgio|G|', 'Cenderello|Giovanni|G|', 'Dentone|Chiara|C|', 'Nicolini|Laura|L|', 'Moretta|Alessandro|A|', 'Moretta|Lorenzo|L|', 'De Maria|Andrea|A|']
D015415:Biomarkers D002454:Cell Differentiation D016207:Cytokines D003587:Cytomegalovirus D003586:Cytomegalovirus Infections D006412:Hematopoietic Stem Cells D054884:Host-Pathogen Interactions D006801:Humans D016130:Immunophenotyping D018836:Inflammation Mediators D007694:Killer Cells, Natural D008213:Lymphocyte Activation D055654:NK Cell Lectin-Like Receptor Subfamily C
viral infection HIV common lymphocyte precursors HCMV HCV Lin(−)CD34(+)DNAM-1(bright) NKG2C Natural killer cells hematopoietic stem cells