METTL3-dependent m⁶A modification programs T follicular helper cell differentiation.

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• T follicular helper (T_FH) cells are vital for effective humoral immunity.
• The role of post-transcriptional regulation, specifically mRNA methylation, in T_FH cell function remains largely unexplored.

Purpose of the Study:

• To investigate the function of METTL3-mediated mRNA N⁶-methyladenosine (m⁶A) modification in T_FH cell differentiation.
• To elucidate the molecular mechanisms by which METTL3 influences T_FH cell development and function.

Main Methods:

• Conditional deletion of METTL3 in CD4⁺ T cells in mice.
• m⁶A-miCLIP-seq to identify m⁶A-modified transcripts.
• Analysis of T_FH cell differentiation and germinal center responses.
• Assessment of Tcf7 mRNA stability and TCF-1 protein expression.

Main Results:

• Conditional deletion of METTL3 in CD4⁺ T cells impaired T_FH differentiation and germinal center responses in a cell-intrinsic manner.
• METTL3 is essential for the expression of key T_FH signature genes, including Tcf7, Bcl6, Icos, and Cxcr5.
• METTL3-dependent m⁶A modification of Tcf7 mRNA's 3' UTR stabilizes the transcript, and its loss accelerates Tcf7 decay.
• Restoring TCF-1 expression rescued T_FH defects caused by METTL3 deficiency.

Conclusions:

• METTL3 plays a critical role in T_FH cell differentiation through the m⁶A modification of Tcf7 mRNA.
• This post-transcriptional regulation ensures the stability of Tcf7 transcripts, thereby promoting the T_FH transcriptional program essential for humoral immunity.