N⁶ - Methyladenosine defines a new checkpoint in γδ T cell development

T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αβ and γδ receptors, T cells are mainly divided into αβ and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well-characterized and different developmental processes. N⁶ -Methyladenosine (m⁶ A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Recently, we have demonstrated that the depletion of m⁶ A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αβ T cells, indicating a checkpoint role of ALKBH5 and m⁶ A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m⁶ A modification. In this review, we mainly summarize the potential regulation between m⁶ A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development.