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

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.