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The GFI1-FOXO1 axis regulates NK cell maturation and function.

Qiutong Huang1,2,3,4, M Zeeshan Chaudhry5, James Dight1

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Growth factor independence 1 (GFI1) is an epigenetic regulator essential for natural killer (NK) cell differentiation. It balances key transcription factors, promoting NK cell maturation and anti-tumour activity by interacting with FOXO1.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • Natural killer (NK) cells are crucial for innate immunity against viral infections and cancer.
  • The transcriptional regulation of NK cell differentiation and maturation is not fully understood.

Purpose of the Study:

  • To identify key transcriptional regulators of NK cell differentiation.
  • To elucidate the role of GFI1 in coordinating NK cell maturation and effector functions.

Main Methods:

  • Paired single-cell multiomic profiling was employed to analyze NK cell differentiation.
  • Chromatin accessibility assays were used to study the epigenetic effects of GFI1 and FOXO1.

Main Results:

  • GFI1 was identified as an epigenetic regulator of NK cell differentiation, balancing EOMES and T-BET.
  • GFI1 promotes NK cell proliferation and the transition to terminally differentiated states by repressing FOXO1.
  • Co-deletion of GFI1 and FOXO1 rescued NK cell differentiation and enhanced protection against tumour metastasis.

Conclusions:

  • GFI1 is a critical transcriptional node integrating NK cell differentiation, activation, and effector programs.
  • The GFI1-FOXO1 axis is essential for NK cell maturation and anti-tumour immunity.