m 6 A demethylase ALKBH5 controls CD4 + T cell pathogenicity and promotes autoimmunity

ALKBH5 maintains CD4 + T cell pathogenicity during autoimmune disease via regulating IFN-γ and CXCL2. N 6 -methyladenosine (m 6 A) modification is dynamically regulated by “writer” and “eraser” enzymes. m 6 A “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 m 6 A 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 m 6 A 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 m 6 A eraser in controlling the pathogenicity of CD4 + T cells during autoimmunity.