METTL3 inhibition reduces N⁶‐methyladenosine levels and prevents allogeneic CD4⁺ T‐cell responses.

Alloreactive CD4+ T cells play a central role in allograft rejection. However, the post‐transcriptional regulation of the effector program in alloreactive CD4+ T cells remains unclear. N6‐methyladenosine (m6A) RNA modification is involved in various physiological and pathological processes. Herein, we investigated whether m6A methylation plays a role in the allogeneic T‐cell effector program. m6A levels of CD4+ T cells from spleens, draining lymph nodes and skin allografts were determined in a skin transplantation model. The effects of a METTL3 inhibitor (STM2457) on CD4+ T‐cell characteristics including proliferation, cell cycle, cell apoptosis and effector differentiation were determined after stimulation of polyclonal and alloantigen‐specific (TEa; CD4+ T cells specific for I‐Eα52‐68) CD4+ T cells with α‐CD3/α‐CD28 monoclonal antibodies and cognate CB6F1 alloantigen, respectively. We found that graft‐infiltrating CD4+ T cells expressed high m6A levels. Administration of STM2457 reduced m6A levels, inhibited T‐cell proliferation and suppressed effector differentiation of polyclonal CD4+ T cells. Alloreactive TEa cells challenged with 40 μm STM2457 exhibited deficits in T‐cell proliferation and T helper type 1 cell differentiation, a cell cycle arrest in the G0 phase and elevated cell apoptosis. Moreover, these impaired T‐cell responses were associated with the diminished expression levels of transcription factors Ki‐67, c‐Myc and T‐bet. Therefore, METTL3 inhibition reduces the expression of several key transcriptional factors for the T‐cell effector program and suppresses alloreactive CD4+ T‐cell effector function and differentiation. Targeting m6A‐related enzymes and molecular machinery in CD4+ T cells represents an attractive therapeutic approach to prevent allograft rejection. [ABSTRACT FROM AUTHOR]

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