METTL14-dependent m⁶A modification controls iNKT cell development and function

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• N6-methyladenosine (m6A) is the most prevalent RNA modification, regulating gene expression.
• m6A controls CD4+ T cell homeostasis via the IL-7/STAT5/SOCS pathway.
• The function of m6A in unconventional T cell development is largely unexplored.

Purpose of the Study:

• To investigate the role of m6A modification, specifically mediated by METTL14, in the development and homeostasis of invariant natural killer T (iNKT) cells.

Main Methods:

• Utilized mice with T cell-specific deletion of the RNA methyltransferase METTL14 (T-Mettl14-/-).
• Analyzed thymocyte apoptosis, Vα14-Jα18 gene rearrangement, and iNKT cell populations in vivo.
• Assessed iNKT cell maturation, responsiveness to cytokine and TCR stimulation, and cytokine production following METTL14 knockdown.

Main Results:

• T-Mettl14-/- mice exhibited increased thymocyte apoptosis and reduced Vα14-Jα18 rearrangements, leading to significantly fewer iNKT cells.
• Residual iNKT cells in T-Mettl14-/- mice showed enhanced apoptosis, impaired maturation, and diminished responsiveness to IL-2/IL-15 and TCR signaling.
• METTL14 knockdown in mature iNKT cells decreased cytokine production, associated with increased Cish expression and impaired TCR signaling.

Conclusions:

• METTL14-dependent m6A modification is essential for iNKT cell development, homeostasis, and function.
• Loss of m6A modification disrupts iNKT cell generation and survival by affecting thymocyte apoptosis and TCR signaling pathways.
• This study establishes m6A RNA modification as a critical regulator of unconventional T cell biology.