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Immunol."],"abstract":"<jats:p>Haploidentical hematopoietic stem cell transplantation (h-HSCT) is a therapeutic option to cure patients affected by hematologic malignancies. The kinetics and the quality of immune-reconstitution (IR) impact the clinical outcome of h-HSCT and limit the onset of life-threatening Human Cytomegalovirus (HCMV) infection\/reactivation. Natural Killer (NK) cells are the first lymphocytes that recover after h-HSCT and they can provide rapid innate immune responses against opportunistic pathogens. By performing a longitudinal single-cell analysis of multiparametric flow-cytometry data, we show here that the persistence at high frequencies of CD158b1b2j<jats:sup>neg<\/jats:sup>\/NKG2A<jats:sup>pos<\/jats:sup>\/NKG2C<jats:sup>neg<\/jats:sup>\/NKp30<jats:sup>pos<\/jats:sup>\/NKp46<jats:sup>pos<\/jats:sup> (KIR<jats:sup>neg<\/jats:sup>) NK cells is associated with HCMV infection\/reactivation control. These KIR<jats:sup>neg<\/jats:sup> NK cells are \u201cunlicensed\u201d, and are not terminal-differentiated lymphocytes appearing early during IR and mainly belonging to CD56<jats:sup>bright<\/jats:sup>\/CD16<jats:sup>neg<\/jats:sup> and CD56<jats:sup>bright<\/jats:sup>\/CD16<jats:sup>pos<\/jats:sup> subsets. KIR<jats:sup>neg<\/jats:sup> NK cells are enriched in oxidative and glucose metabolism pathways, produce interferon-\u03b3, and are endowed with potent antiviral activity against HCMV <jats:italic>ex vivo<\/jats:italic>. Decreased frequencies of KIR<jats:sup>neg<\/jats:sup> NK cells early during IR are associated with clinically relevant HCMV replication. Taken together, our findings indicate that the prolonged persistence of KIR<jats:sup>neg<\/jats:sup> NK cells after h-HSCT could serve as a biomarker to better predict HCMV infection\/reactivation. This phenomenon also paves the way to optimize anti-viral immune responses by enriching post-transplant donor lymphocyte infusions with KIR<jats:sup>neg<\/jats:sup> NK cells.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1266051","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T04:18:06Z","timestamp":1704860286000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Persistence of KIRneg NK cells after haploidentical hematopoietic stem cell transplantation protects from human cytomegalovirus infection\/reactivation"],"prefix":"10.3389","volume":"14","author":[{"given":"Clara","family":"Di 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