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

2021; Elsevier BV; Volume: 147; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2020.12.648

1097-6825

Federica Bozzano, Mariella Della Chiesa, Andrea Pelosi, Francesca Antonini, Maria Libera Ascierto, Genny Del Zotto, Francesca Moretta, Letizia Muccio, Anna Luganini, Giorgio Gribaudo, Giovanni Cenderello, Chiara Dentone, Laura Ambra Nicolini, Alessandro Moretta, Lorenzo Moretta, Andrea De Maria,

CAR-T cell therapy research

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