RNA m <sup>6</sup> A demethylase ALKBH5 regulates the development of γδ T cells
Chenbo Ding, Hao Xu, Zhibin Yu, Manolis Roulis, Rihao Qu, Jing Zhou, Joonseok Oh, Jason M. Crawford, Yimeng Gao, Ruaidhrí Jackson, Esen Sefik, Simiao Li‐Sauerwine, Zheng Wei, Mathias Skadow, Zhinan Yin, Xinshou Ouyang, Lei Wang, Qiang Zou, Bing Su, Weiguo Hu, Richard A. Flavell, Huabing Li
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. 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 γδ 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 γδ T cells, which confers enhanced protection against gastrointestinal Salmonella 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.