The ascorbate-Tet axis is a checkpoint regulator of naive T-cell quiescence 2257733
T-cell peripheral tolerance is crucial for maintaining immune homeostasis and preventing autoimmunity, which is characterized by limited response of conventional T cells to antigen stimulation. The mechanisms controlling this process remain to be fully elucidated. To investigate the role of nutritional factors and related epigenetic mechanisms, we conducted in vivo CRISPR screening and identified ascorbate transporter Slc23a2. Ablation of Slc23a2 in T cells decreases intracellular ascorbate levels, leading to DNA hypermethylation in specific regions. This results in increased differentiation of naive T (Tn) cells into effector and memory T cells, accompanied by low-grade autoimmune inflammation, which is comparable to ascorbate deprivation, Tet dioxygenase deletion, and aged T cells. Mechanistically, Slc23a2 through ascorbate activates Tet methylcytosine dioxygenases to restrict Tn cell activation and differentiation into effector or memory T cells by attenuating TCR signaling, reducing helper T-cell determinants, and enhancing Tcf1 expression and chromatin binding. Tcf1 ablation partially mimics Slc23a2 deficiency, while Tcf1 overexpression suppresses its effect. Therefore, the ascorbate-Tet axis functions as a checkpoint regulator for Tn quiescence, ensuring peripheral tolerance, particularly during aging. N/A Immune Response Regulation: Cellular Mechanisms (IRC)