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The N6-methyladenosine writer WTAP contributes to the induction of immune tolerance post kidney transplantation by targeting regulatory T cells

Abstract

N6-methyladenosine (m6A) modification is involved in diverse immunoregulation, while the relationship between m6A modification and immune tolerance post kidney transplantation remains unclear. Expression of Wilms tumor 1-associating protein (WTAP), an m6A writer, was firstly detected in tolerant kidney transplant recipients (TOL). Then the role of WTAP on regulatory T (Treg) cell differentiation and function in CD4+ T cells from kidney transplant recipients with immune rejection (IR) was investigated. The potential target of WTAP and effect of WTAP on immune tolerance in vivo were subsequently verified. WTAP was upregulated in CD4+ T cells of TOL and positively correlated with Treg cell proportion. In vitro, WTAP overexpression promoted Treg cell differentiation and enhanced Treg cell-mediated suppression toward naïve T cells. Forkhead box other 1 (Foxo1) was identified as a target of WTAP. WTAP enhanced m6A modification of Foxo1 mRNA in coding sequence (CDS) region, leading to up-regulation of Foxo1. Overexpression of m6A demethylase removed the effect of WTAP overexpression, while Foxo1 overexpression reversed these effects. WTAP overexpression alleviated allograft rejection in model mice, as evidenced by reduced inflammatory response and increased Treg population. Our study suggests that WTAP plays a positive role in induction of immune tolerance post kidney transplant by promoting Treg cell differentiation and function.

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Fig. 1: Correlation between the expression of Wilms tumor 1-associating protein (WTAP) and regulatory T (Treg) cell proportion in peripheral blood CD4+ T cells of tolerant kidney transplant recipients (TOL).
Fig. 2: The effect of WTAP overexpression on Treg cell differentiation and function.
Fig. 3: The mechanism by which WTAP overexpression enhanced forkhead box other 1 (Foxo1) expression.
Fig. 4: WTAP promoted Foxo1 translation depend on m6A methylation in CDS region.
Fig. 5: The effect of WTAP overexpression on allograft rejection in kidney transplant model mice.
Fig. 6: Schematic diagram of WTAP affecting Treg differentiation and function.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by the Medical Science and Technology Research Project of Henan Province (No. SB201901004).

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WZ: Conceptualization, funding acquisition, data analysis; QY: data analysis, major revision; FY: Conceptualization, writing-original draft; XH & WJ & ZL: methodology, data curation; ZJ & HX: methodology, formal analysis; FG: Conceptualization, project administration; SW: Conceptualization, supervision, validation, writing-review, and editing. All authors reviewed and approved the final manuscript.

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Correspondence to Zhigang Wang, Guiwen Feng or Wenjun Shang.

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The authors declare no competing interests.

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This study was approved by the Ethics Committee of The First Affiliated Hospital of Zhengzhou University.

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Wang, Z., Qi, Y., Feng, Y. et al. The N6-methyladenosine writer WTAP contributes to the induction of immune tolerance post kidney transplantation by targeting regulatory T cells. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00811-w

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