RNA m6A demethylase ALKBH5 regulates the development of γδ T cells

Abstract γδ T cells are abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells origin in thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. N 6 -methyladenosine (m 6 A) represents one of the most common post-transcriptional modifications of mRNA in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here we show that depletion of m 6 A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal S. typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of m 6 A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2 . As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m 6 A modification in the regulation of γδ T cell early development.