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N6-adenosine methylation (m6A) is involved in the life and death decisions of T cells

Cellular & Molecular Immunology volume 20, pages 316–317 (2023)Cite this article

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N6-adenosine methylation (m6A) is the most abundant modification observed in mRNA transcripts. It is a dynamic modification that is performed by members of the so-called writer complex (including Wtap, Virma and Mettl3) and that can be removed by so-called eraser proteins [1]. In addition, m6A is recognized by reader proteins (including Ythdf2) that can exert a response. Readers and m6A can modify virtually all mRNA processes, including RNA splicing, secondary structures, nuclear export and transcript stability [1]. The functional relevance of m6A-mediated regulation in specific cell types and treatment conditions remains only partly understood. In T cells, earlier studies have demonstrated a relevant role for m6A in T effector (Teff), T follicular helper (TFH) and T regulatory (Treg) cells through manipulation of m6A pathway genes in mice [2,3,4,5,6]. In these studies, disruption of m6A resulted in dysregulation of gene expression patterns and caused colitis and systemic autoinflammatory disease. In a recent study by Ito-Kureha et al., the authors set out to further understand how m6A signaling affects T-cell functions by manipulating Wtap in select T cells with a murine knockout model [7]. They found that m6A signaling controls many aspects of T-cell immunobiology: activation, proliferation, life, and death.

The researchers first assessed the role of Wtap in T cells. Therefore, Ito-Kureha et al. developed an elegant Cre-conditional Wtap knockout mouse model. In this model, Wtap was knocked out in either (nearly) all T cells (CD4-Cre) or in Treg cells specifically (Foxp3-Cre) [7]. The Wtap knockout in all T cells resulted in a colitis phenotype in line with earlier observations [5]. Treg-specific knockout showed increased expression of RORgt and IL-17a in Treg cells and associated systemic inflammation. Several experiments have shown that Wtap is involved in TCR signaling and the response to activation. In Wtap−/− T cells, the authors reported altered thymocyte differentiation patterns and Treg induction, a reduced proliferative response to lymphopenia, and increased activation and cell death after CD3/CD28 stimulation. These results indicate a regulatory role for Wtap in TCR signaling, as well as a role in regulating cell death in activated proliferating T cells.

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  1. These authors contributed equally: J.J.A. Calis, J. van Loosdregt.

Authors and Affiliations

  1. Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    J. J. A. Calis & J. van Loosdregt

  2. Pediatric Immunology & Rheumatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands

    J. J. A. Calis

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Correspondence to J. van Loosdregt.

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Calis, J.J.A., van Loosdregt, J. N6-adenosine methylation (m6A) is involved in the life and death decisions of T cells. Cell Mol Immunol 20, 316–317 (2023). https://doi.org/10.1038/s41423-022-00958-y

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