SNP rs10748643 determines CD39 expression in T and NK cells through altering NFIC binding affinity rather than...

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• CD39 (NTPDase-1) is crucial for purinergic signaling and regulates immune cell function, particularly T cells.
• Single-nucleotide polymorphism (SNP) rs10748643 is often used to infer CD39 expression levels in T cells.
• The impact of this SNP on CD39 expression across all immune cell types remains uncharacterized.

Purpose of the Study:

• To investigate the effect of SNP rs10748643 on CD39 expression in six major immune cell types.
• To elucidate the molecular mechanisms underlying the SNP's influence on CD39 regulation.
• To explore potential therapeutic strategies targeting CD39 expression.

Main Methods:

• Flow cytometry was used to quantify CD39 expression across different genotypes in T cells, natural killer (NK) cells, monocytes, B cells, and granulocytes.
• Bioinformatic analyses and bench experiments were employed to explore underlying genetic and regulatory mechanisms.
• Cleavage Under Targets and Tagmentation (CUT&Tag) technology was utilized to assess transcription factor binding affinity.

Main Results:

• SNP rs10748643 significantly influences CD39 expression in T and NK cells, but has minimal impact on monocytes, B cells, and granulocytes.
• Monocytes, B cells, and granulocytes exhibit constitutive CD39 expression, distinct from T and NK cells.
• The SNP affects CD39 mRNA variants differently in T cells compared to B cells, ruling out splicing efficiency as the primary mechanism.
• NFIC transcription factor binding affinity to the CD39 promoter decreases with the A-to-G SNP mutation, reducing NFIC-mediated inhibition of CD39 expression in T cells.

Conclusions:

• SNP rs10748643 is a key determinant of CD39 expression specifically in T and NK cells.
• The mechanism involves altered binding of the transcription factor NFIC to the CD39 promoter region.
• Targeting NFIC or its inducers presents a potential strategy for modulating CD39 expression and improving the immunosuppressive tumor microenvironment.