RNA m6A demethylase ALKBH5 regulates the development of γδ 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.

Automated summary

This study found that ALKBH5 and m(6)A modification are involved in the development of γδT cells. Depletion of ALKBH5 leads to an expansion of γδT cells, resulting in enhanced protection against Salmonella typhimurium infection in the gastrointestinal tract. This is attributed to the increased development of γδT cell precursors and the reduced expression of target genes in the Notch signaling pathway.