RNA m(6)A demethylase ALKBH5 regulates the development of gamma delta T cells

gamma delta 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 gamma delta T cells' origin in the thymus, detailed mechanisms regulating gamma delta T cell development remain poorly understood. N-6-methyladenosine (m(6)A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in gamma delta T cell biology is still unclear. Here, we show that depletion of the m(6)A demethylase ALKBH5 in lymphocytes specifically induces an expansion of gamma delta T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of gamma delta 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 gamma delta T cell precursors, leading to an expanded mature gamma delta T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m(6)A modification in the regulation of gamma delta T cell early development.