title: Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies.
abstract: We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.
authors.affiliation: Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Muccio
authors.affiliation: Dipartimento di Oncoematologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bertaina
authors.affiliation: IRCCS, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Falco
authors.affiliation: IRCCS, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.affiliation: IRCCS, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meazza
authors.affiliation: Universitat Pompeu Fabra and Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lopez-Botet
authors.affiliation: Dipartimento di Immunologia, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Dipartimento di Oncoematologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Pediatrico Bambino Gesù, Roma, Italy Dipartimento di Scienze Pediatriche, Università di Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Italy alemoret@unige.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.affiliation: Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Della Chiesa
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018959:CD57 Antigens / Q000235:genetics / Q000276:immunology; D002648:Child; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation; D019337:Hematologic Neoplasms / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007156:Immunologic Memory; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008212:Lymphocyte Depletion; D008297:Male; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D018959:CD57 Antigens; D020382:Interleukin-18; C527059:KLRC2 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054340:Receptors, KIR; D018664:Interleukin-12