m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity

Abstract

N⁶-methyladenosine (m⁶A) modification is dynamically regulated by "writer" and "eraser" enzymes. m⁶A "writers" have been shown to ensure the homeostasis of CD4⁺ T cells, but the "erasers" functioning in T cells is poorly understood. Here, we reported that m⁶A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4⁺ T cells to induce adoptive transfer colitis. In addition, T cell-specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m⁶A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4⁺ T cells. These modifications resulted in attenuated CD4⁺ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m⁶A eraser in controlling the pathogenicity of CD4⁺ T cells during autoimmunity.