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The existence of N 6 -adenosine methylation (m 6 A) of mRNA has been known for a long time, but only recently its regulatory potential was uncovered. Current research deciphers the molecular determinants leading to the deposition of this modification and consequences for modified mRNAs. It also evaluates the importance of such modifications for specific cell types and programs. In this review, we summarize the current knowledge on m 6 A modification of mRNAs in conventional and regulatory T cells and T-cell-driven immune responses and pathology. We discuss the impact of m 6 A modification on T cell activation including cytokine and antigen receptor signaling or sensing of double-stranded RNAs (dsRNA)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Post-transcriptional gene regulation by RNA-binding proteins controls mRNA half-life and efficiency of translation. Recently, the RNA-binding proteins Roquin and Regnase-1 have been shown to play pivotal roles in T lymphocytes by preventing inflammatory and autoimmune disease. These factors share an overlapping set of target mRNAs and are both regulated by proteolytic cleavage through the paracaspase MALT1. This review discusses the mouse models of inactivation or deregulation and how these trans-acting factors recognize target mRNAs. Based on different affinities of cis-elements in target mRNAs and regulation of the trans-acting factors, we propose the following model: Increasing TCR signal strength will gradually inactivate Roquin and Regnase-1 causing differential target mRNA derepression that specifies cell fate decisions and effector functions of T cells., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Natural killer (NK) cells play a critical role in early host defense to infected and transformed cells. Here, we show that mice deficient in Eri1, a conserved 3'-to-5' exoribonuclease that represses RNA interference, have a cell-intrinsic defect in NK-cell development and maturation. Eri1(-/-) NK cells displayed delayed acquisition of Ly49 receptors in the bone marrow (BM) and a selective reduction in Ly49D and Ly49H activating receptors in the periphery. Eri1 was required for immune-mediated control of mouse CMV (MCMV) infection. Ly49H(+) NK cells deficient in Eri1 failed to expand efficiently during MCMV infection, and virus-specific responses were also diminished among Eri1(-/-) T cells. We identified miRNAs as the major endogenous small RNA target of Eri1 in mouse lymphocytes. Both NK and T cells deficient in Eri1 displayed a global, sequence-independent increase in miRNA abundance. Ectopic Eri1 expression rescued defective miRNA expression in mature Eri1(-/-) T cells. Thus, mouse Eri1 regulates miRNA homeostasis in lymphocytes and is required for normal NK-cell development and antiviral immunity.

MicroRNA (miRNA) target predictions support a view in which each miRNA regulates translation and stability of several hundred messenger RNAs (mRNAs). Studies that overexpress individual miRNAs typically uncover relative subtle inhibition of the predicted targets. Accordingly, most miRNAs expressed in a given cell type may serve the function to broadly inhibit cell-type-inappropriate gene expression and deepen a pre-existing differentiation program. However, recent functional analyses of miRNAs in the immune system reveal that many cellular decisions are controlled by single miRNAs that entail significant downregulation of one or few target proteins. Investigations of these miRNA/mRNA pairs showed that miRNA-adjusted target protein levels are crucial at specific cellular transition points. Here, we will review recent advances in the regulation of the miRNA pathway and discuss how miRNAs control immune functions.