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IKAROS regulates human T cell phenotype at a thymic and postthymic level.

Jennifer Stoddard1, Hye Sun Kuehn1, Ravichandra Tagirasa1

  • 1Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA.

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|December 22, 2025
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Summary

The transcription factor IKAROS (IKZF1) regulates T cell development by modulating HNRNPLL, which controls naive and memory T cell phenotypes. This finding clarifies IKAROS

Keywords:
Cell biologyGeneticsImmunologyT cells

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Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • The transcription factor IKAROS (IKZF1) is essential for lymphocyte development.
  • IKZF1 mutations lead to immunodeficiencies and altered T cell phenotypes, including shifts in naive and memory T cell populations.
  • Different IKZF1 variants (haploinsufficiency, dominant-negative) cause distinct T cell developmental defects.

Purpose of the Study:

  • To elucidate the role of IKAROS in shaping human naive and memory T cell phenotypes.
  • To investigate the molecular mechanisms by which IKAROS influences T cell differentiation.
  • To analyze early T cell development in an artificial thymic organoid (ATO) system using patient-derived cells.

Main Methods:

  • IKAROS immunomodulation using lenalidomide and knockdown via small hairpin RNA.
  • Analysis of T cell development in an artificial thymic organoid (ATO) system using CD34+ cells from patients with IKZF1 variants.
  • Assessment of CD45 isoform splicing regulator HNRNPLL expression.
  • Analysis of public gene expression data.

Main Results:

  • IKAROS inhibition or silencing directly altered HNRNPLL expression, the regulator of CD45 isoforms defining naive (CD45RA+) and memory (CD45RO+) T cells.
  • In the ATO system, IKAROS-dominant-negative precursor cells arrested at the double-negative stage with a CD45RA+ phenotype.
  • IKAROS-haploinsufficient cells showed inefficient progression to the double-positive stage and partial CD45RA to CD45RO transition.
  • High HNRNPLL expression was observed in double-positive thymic cells, extending beyond the stages affected by IKZF1 mutations.

Conclusions:

  • IKAROS regulates both early and late stages of human T cell development.
  • IKAROS exerts its regulatory function partly through the modulation of HNRNPLL.
  • Understanding IKAROS's role provides insights into T cell immunodeficiencies and potential therapeutic targets.