Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents an efficient curative approach for patients affected by hematologic malignancies in which the reduced intensity conditioning induces a state of immunologic tolerance between donor and recipient. However, opportunistic viral infections greatly affect h-HSCT clinical outcomes. NK cells are the first lymphocytes that recover after transplant and provide a prompt defense against human cytomegalovirus (HCMV) infection/reactivation. By undertaking a longitudinal single-cell computational profiling of multiparametric flow cytometry, we show that HCMV accelerates NK cell immune reconstitution together with the expansion of CD158b1b2jpos/NKG2Aneg/NKG2Cpos/ NKp30lo NK cells. The frequency of this subset correlates with HCMV viremia, further increases in recipients experiencing multiple episodes of viral reactivations, and persists for months after the infection. The transcriptional profile of FACS-sorted CD158b1b2jpos NK cells confirmed the ability of HCMV to deregulate NKG2C, NKG2A, and NKp30 gene expression, thus inducing the expansion of NK cells with adaptive traits. These NK cells are characterized by the downmodulation of several gene pathways associated with cell migration, the cell cycle, and effector-functions, as well as by a state of metabolic/cellular exhaustion. This profile reflects the functional impairments of adaptive NK cells to produce IFN-γ, a phenomenon also due to the viral-induced expression of lymphocyteactivation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) checkpoint inhibitors.

Single-cell profiling identifies impaired adaptive NK cells expanded after HCMV reactivation in haploidentical HSCT / E. Zaghi, M. Calvi, S. Puccio, G. Spata, S. Terzoli, C. Peano, A. Roberto, F. De Paoli, J.J.P. van Beek, J. Mariotti, C. De Philippis, B. Sarina, R. Mineri, S. Bramanti, A. Santoro, V.T.K. Le-Trilling, M. Trilling, E. Marcenaro, L. Castagna, C. Di Vito, E. Lugli, D. Mavilio. - In: JCI INSIGHT. - ISSN 2379-3708. - 6:12(2021 Jun 22), pp. e146973.1-e146973.19. [10.1172/jci.insight.146973]

Single-cell profiling identifies impaired adaptive NK cells expanded after HCMV reactivation in haploidentical HSCT

J. Mariotti;C. De Philippis;L. Castagna;C. Di Vito;D. Mavilio
Writing – Original Draft Preparation
2021

Abstract

Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents an efficient curative approach for patients affected by hematologic malignancies in which the reduced intensity conditioning induces a state of immunologic tolerance between donor and recipient. However, opportunistic viral infections greatly affect h-HSCT clinical outcomes. NK cells are the first lymphocytes that recover after transplant and provide a prompt defense against human cytomegalovirus (HCMV) infection/reactivation. By undertaking a longitudinal single-cell computational profiling of multiparametric flow cytometry, we show that HCMV accelerates NK cell immune reconstitution together with the expansion of CD158b1b2jpos/NKG2Aneg/NKG2Cpos/ NKp30lo NK cells. The frequency of this subset correlates with HCMV viremia, further increases in recipients experiencing multiple episodes of viral reactivations, and persists for months after the infection. The transcriptional profile of FACS-sorted CD158b1b2jpos NK cells confirmed the ability of HCMV to deregulate NKG2C, NKG2A, and NKp30 gene expression, thus inducing the expansion of NK cells with adaptive traits. These NK cells are characterized by the downmodulation of several gene pathways associated with cell migration, the cell cycle, and effector-functions, as well as by a state of metabolic/cellular exhaustion. This profile reflects the functional impairments of adaptive NK cells to produce IFN-γ, a phenomenon also due to the viral-induced expression of lymphocyteactivation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) checkpoint inhibitors.
bone marrow transplantation; hematology; immunology; innate immunity; NK cells
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
Settore MED/04 - Patologia Generale
Settore MED/06 - Oncologia Medica
Settore MED/15 - Malattie del Sangue
Article (author)
File in questo prodotto:
File Dimensione Formato  
C:Zaghi E. et al. JCI Insights.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 6.85 MB
Formato Adobe PDF
6.85 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/860491
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 7
social impact