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

Jing Zhou; Xingli Zhang; Jiajia Hu; Rihao Qu; Zhibin Yu; Hao Xu; Huifang Chen; Lichong Yan; Chenbo Ding; Qiang Zou; Youqiong Ye; Zhengting Wang; Richard A Flavell; Hua-Bing Li

doi:10.1126/sciadv.abg0470

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

Sci Adv. 2021 Jun 16;7(25):eabg0470. doi: 10.1126/sciadv.abg0470. Print 2021 Jun.

Authors

Jing Zhou^{1

2

3}, Xingli Zhang^{1

2}, Jiajia Hu⁴, Rihao Qu^{5

6}, Zhibin Yu^{1

2}, Hao Xu³, Huifang Chen^{1

2}, Lichong Yan³, Chenbo Ding^{1

2

3}, Qiang Zou¹, Youqiong Ye¹, Zhengting Wang⁷, Richard A Flavell^{8

9}, Hua-Bing Li^{10

2

3}

Affiliations

¹ Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8055, USA.
⁴ Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁵ Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
⁶ Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA.
⁷ Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁸ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8055, USA. huabing.li@shsmu.edu.cn richard.flavell@yale.edu.
⁹ Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8055, USA.
¹⁰ Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. huabing.li@shsmu.edu.cn richard.flavell@yale.edu.

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.

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