Post Doc St Jude Children's Research hospital Memphis, Tennessee, United States
Introduction/Rationale: 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.
Methods: To investigate the role of nutritional factors and related epigenetic mechanisms, we conducted in vivo CRISPR screening and identified ascorbate transporter Slc23a2.
Results: 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.
Conclusion: Therefore, the ascorbate-Tet axis functions as a checkpoint regulator for Tn quiescence, ensuring peripheral tolerance, particularly during aging.
