METTL14-dependent m⁶A modification controls iNKT cell development and function.

ABSTRACT: N⁶-methyladenosine (m⁶A), the most common form of RNA modification, controls CD4⁺ T cell homeostasis by targeting the IL-7/STAT5/SOCS signaling pathways. The role of m⁶A modification in unconventional T cell development remains unknown. Using mice with T cell-specific deletion of RNA methyltransferase METTL14 (T-Mettl14^-/-), we demonstrate that m⁶A modification is indispensable for iNKT cell homeostasis. Loss of METTL14-dependent m⁶A modification leads to the upregulation of apoptosis in double-positive thymocytes, which in turn decreases Vα14-Jα18 gene rearrangements, resulting in drastic reduction of iNKT numbers in the thymus and periphery. Residual T-Mettl14^-/- iNKT cells exhibit increased apoptosis, impaired maturation, and decreased responsiveness to IL-2/IL-15 and TCR stimulation. Furthermore, METTL14 knockdown in mature iNKT cells diminishes their cytokine production, correlating with increased Cish expression and decreased TCR signaling. Collectively, our study highlights a critical role for METTL14-dependent-m⁶A modification in iNKT cell development and function.

SUBMITTER: Cao L 

PROVIDER: S-EPMC9495716 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature