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. 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.

N6‐ Methyladenosine defines a new checkpoint in γδ T cell development

“…(Table 1). [49] Our previous works have shown that m 6 A writer METTL3 deletion has much greater impact on the development and function of T cells compared with that of m 6 A eraser ALKBH5 deletion or FTO deletion. [46,108] Though the level of m Notably, it has shown that these effects of Notch signaling in pre-T cells are mediated by the Akt activity.…”

“…[107] Jag1/Notch2 ALKBH5 regulates γδ T cell development through Jag1/Notch2 signaling. [49] Akt METTL3 and METTL14 suppress Akt signaling by destabilizing mRNAs of Akt activators, while increasing translational efficiency of Akt suppressors. [111,112]…”

“…[96] Based on our previous work, Runx3 and HES1 are significantly decreased in the absence of ALKBH5 in γδ T cell precursors. [49] Though there are no papers about the direct crosstalk between Sox13 and m 6 A modification, Sox13 transcript is found to have m 6 A peaks in Fto-deficient mice (Table 1). [97] And other studies also demonstrate that Sox13 has highly enriched and specific m 6 A peaks in fetal intestine.…”

“…[22] Recently, we have found that the depletion of ALKBH5 in the lymphocytes specifically enhances the proliferation and differentiation of γδ T cell precursor, not in αβ T cells, and is responsible for a significant expansion of γδ T cells starting at the embryonic stage. [49] In this review, we mainly summarize the key target pathways and molecules regulated by m 6 A modification in the development and fate choice of αβ T vs γδ T cells, to provide potential scientific basis and regulatory modes for m 6 A modification in the checkpoint of γδ T cell development.…”

m6A methylation: a process reshaping the tumour immune microenvironment and regulating immune evasion

“…A recent study discovered that deletion of the m 6 A demethylase ALKBH5 in lymphocytes enhances γδT-cell expansion. Mechanistically, increased m 6 A levels in thymocytes reduce the transcript abundance of target genes in Notch signalling, contributing to the augment of γδT cell proliferation and differentiation [ 201 ] (Fig. 3 ).…”