RNA m ⁶ A demethylase ALKBH5 regulates the development of γδ T cells

Abstract

γδ 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 γδ T cells' origin in the thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. <i>N</i>⁶-methyladenosine (m⁶A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here, we show that depletion of the m⁶A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal <i>Salmonella typhimurium</i> infection. Mechanistically, loss of ALKBH5 favors the development of γδ 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 <i>Jagged1</i> and <i>Notch2</i>. 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 m⁶A modification in the regulation of γδ T cell early development.