Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Blood. 2022 Feb 3;139(5):704-716. doi: 10.1182/blood.2021013233.


Neutrophils have been thought to play a critical role in terminal differentiation of NK cells. Whether this effect is direct or a consequence of global immune changes with effects on NK-cell homeostasis remains unknown. In this study, we used high-resolution flow and mass cytometry to examine NK-cell repertoires in 64 patients with neutropenia and 27 healthy age- and sex-matched donors. A subgroup of patients with chronic neutropenia showed severely disrupted NK-cell homeostasis manifesting as increased frequencies of CD56bright NK cells and a lack of mature CD56dim NK cells. These immature NK-cell repertoires were characterized by expression of the proliferation/exhaustion markers Ki-67, Tim-3, and TIGIT and displayed blunted tumor target cell responses. Systems-level immune mapping revealed that the changes in immunophenotypes were confined to NK cells, leaving T-cell differentiation intact. RNA sequencing of NK cells from these patients showed upregulation of a network of genes, including TNFSF9, CENPF, MKI67, and TOP2A, associated with apoptosis and the cell cycle, but different from the conventional CD56bright signatures. Profiling of 249 plasma proteins showed a coordinated enrichment of pathways related to apoptosis and cell turnover, which correlated with immature NK-cell repertoires. Notably, most of these patients exhibited severe-grade neutropenia, suggesting that the profoundly altered NK-cell homeostasis was connected to the severity of their underlying etiology. Hence, although our data suggest that neutrophils are dispensable for NK-cell development and differentiation, some patients displayed a specific gap in the NK repertoire, associated with poor cytotoxic function and more severe disease manifestations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • Female
  • Hepatitis A Virus Cellular Receptor 2 / analysis
  • Homeostasis
  • Humans
  • Infant
  • Ki-67 Antigen / analysis
  • Killer Cells, Natural / pathology*
  • Male
  • Middle Aged
  • Neutropenia / pathology*
  • Receptors, Immunologic / analysis
  • Severity of Illness Index
  • Young Adult


  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Ki-67 Antigen
  • Receptors, Immunologic
  • TIGIT protein, human