RNA m6A demethylase ALKBH5 regulates the developmentof γδ T cells.

γ^δ T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γ^δ T cells' origin in the thymus, detailed mechanisms regulating γ^δ T cell development remain poorly understood. N6-methyladenosine (m⁶A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γ^δ T cell biology is still unclear. Here, we show that depletion of the m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γ^δ T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γ^δ T cell precursors by increasing the abundance of m⁶A 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 γ^δ T cell precursors, leading to an expanded mature γ^δ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m6A modification in the regulation of γ^δ T cell early development. [ABSTRACT FROM AUTHOR]