m⁶A mRNA modification potentiates Th17 functions to inflame autoimmunity

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• N⁶-methyladenosine (m⁶A) is the most prevalent RNA modification, influencing gene expression and cellular processes.
• METTL3, an m⁶A methyltransferase, is known to regulate T cell homeostasis and regulatory T cell function.
• The role of METTL3 in T helper 17 (Th17) cells, critical for immunity and autoimmunity, remains largely unexplored.

Purpose of the Study:

• To investigate the function of METTL3 in Th17 cell differentiation and its role in autoimmune diseases.
• To elucidate the molecular mechanisms by which METTL3 regulates Th17 cell activity.

Main Methods:

• Generation of Mettl3^f/fIl17a^Cre mice for conditional METTL3 deletion in Th17 cells.
• Assessment of Th17 cell differentiation and experimental autoimmune encephalomyelitis (EAE) development.
• Analysis of IL-17A, CCR5, and SOCS3 mRNA expression and stability in Th17 cells.

Main Results:

• METTL3 deficiency in T cells severely impaired Th17 cell differentiation.
• Mettl3^f/fIl17a^Cre mice exhibited reduced EAE severity and decreased Th17 cell infiltration into the central nervous system (CNS).
• METTL3 depletion attenuated IL-17A and CCR5 expression by enhancing SOCS3 mRNA stability, disrupting Th17 cell function.

Conclusions:

• m⁶A modification mediated by METTL3 is essential for maintaining Th17 cell function.
• METTL3 plays a significant role in the pathogenesis of Th17 cell-mediated autoimmune diseases like EAE.
• Targeting METTL3 offers a potential therapeutic strategy for Th17 cell-driven autoimmune conditions.