PRDM1 decreases sensitivity of human NK cells to IL2-induced cell expansion by directly repressing CD25 (IL2RA)


Akman B., Hu X., Liu X., Hatipoglu T., You H., Chan W. C., ...More

JOURNAL OF LEUKOCYTE BIOLOGY, vol.109, no.5, pp.901-914, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 109 Issue: 5
  • Publication Date: 2021
  • Doi Number: 10.1002/jlb.2a0520-321rr
  • Journal Name: JOURNAL OF LEUKOCYTE BIOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.901-914
  • Keywords: CD25, IL2 signaling, IL2R&#945, NK cell expansion, PRDM1, TUMOR-SUPPRESSOR GENE, NATURAL-KILLER-CELLS, TRANSCRIPTIONAL REPRESSOR, IL-2 RECEPTOR, CUTTING EDGE, BLIMP-1, INTERLEUKIN-2, ACTIVATION, EXPRESSION, SEQ
  • Dokuz Eylül University Affiliated: Yes

Abstract

IL2 receptor signaling is crucial for human NK cell activation and gain of effector functions. The molecular mechanisms involved in termination of IL2 activation are largely unknown in human NK cells. PR/SET domain was previously reported to decrease cell growth and increase apoptosis in an IL2-dependent manner in malignant NK cell lines, suggesting the possibility of down-regulation of IL2 signaling pathway gene(s) through direct transcriptional repression. Using ChIP-Seq, we identified a PRDM1 binding site on the first intron of CD25 (IL2RA), which codes for the IL2 receptor subunit regulating sensitivity to IL2 signaling, in primary NK cells activated with engineered K562 cells or IL2. Ectopic expression of PRDM1 down-regulated CD25 expression at transcript and protein levels in two PRDM1 nonexpressing NK cell lines. shRNA-mediated knockdown of CD25 in two malignant NK cell lines led to progressive depletion of NK cells in low IL2 concentrations. By contrast, ectopic CD25 expression in primary human NK cells led to progressive increase in cell number in CD25-transduced cells in low IL2 concentrations. Altogether these results reveal a pivotal role of PRDM1 in inhibition of IL2-induced NK cell expansion through direct repression of CD25 in activated human NK cells. These observations provide additional support for the role of PRDM1 in attenuation of NK cell activation and growth, with implications on neoplastic transformation or NK cell function when it is deregulated.