YTHDF2 suppresses the plasmablast genetic program and promotes germinal center formation

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• B cell differentiation is key to antibody-mediated immunity, leading to plasmablast, memory, and germinal center (GC) cells.
• Transcription factors regulate B cell fate, but early fate determination mechanisms remain largely unknown.

Purpose of the Study:

• To identify and characterize post-transcriptional mechanisms governing early B cell fate decisions.
• To elucidate how B cell differentiation is directed towards germinal center (GC) B cell commitment.

Main Methods:

• Single-cell RNA-sequencing was employed to analyze gene expression in B cell precursors.
• Ythdf2-deficient B cells were studied to assess the role of YTHDF2 in B cell differentiation.
• Analysis of methylated transcripts and YTHDF2 binding was performed.

Main Results:

• Antigen-specific B cell precursors upregulate YTHDF2 at the pre-GC stage.
• YTHDF2 promotes the decay of methylated transcripts, suppressing the plasmablast genetic program.
• Ythdf2-deficient B cells failed to differentiate into GC B cells, despite normal proliferation and activation.

Conclusions:

• YTHDF2 mediates a critical post-transcriptional regulatory mechanism for B cell fate commitment.
• Suppression of the plasmablast program by YTHDF2 is essential for germinal center B cell development.
• This mechanism ensures appropriate B cell fate decisions during the initiation of adaptive immune responses.