Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma

Stem Cell Reports. 2021 Aug 10;16(8):1999-2013. doi: 10.1016/j.stemcr.2021.06.008. Epub 2021 Jul 8.

Abstract

Hematopoietic stem cell transplantation (HSCT) is a frequent therapeutic approach to restore hematopoiesis in patients with hematologic diseases. Patients receive a hematopoietic stem cell (HSC)-enriched donor cell infusion also containing immune cells, which may have a beneficial effect by eliminating residual neoplastic cells. However, the effect that donor innate immune cells may have on the donor HSCs has not been deeply explored. Here, we evaluate the influence of donor natural killer (NK) cells on HSC fate, concluded that NK cells negatively affect HSC frequency and function, and identified interferon-gamma (IFNγ) as a potential mediator. Interestingly, improved HSC fitness was achieved by NK cell depletion from murine and human donor infusions or by blocking IFNγ activity. Thus, our data suggest that suppression of inflammatory signals generated by donor innate immune cells can enhance engraftment and hematopoietic reconstitution during HSCT, which is particularly critical when limited HSC numbers are available and the risk of engraftment failure is high.

Keywords: C/EBPgamma; hematopoietic stem cell; hematopoietic stem cell transplantation; interferon-gamma; natural killer cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / immunology
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cells, Cultured
  • Coculture Techniques
  • Gene Expression Profiling / methods
  • Graft Survival / genetics
  • Graft Survival / immunology
  • Hematopoietic Stem Cell Transplantation / methods*
  • Hematopoietic Stem Cells / immunology*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Depletion / methods
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Tissue Donors*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Cebpg protein, mouse
  • Interferon-gamma