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)
Xiaolei Hao, Lu Bai, Jun Li et al.· Journal of Immunology· 0 citations
Acute myeloid leukemia (AML) represents a type of malignant hematological disease that is usually caused by the dysregulated developmental program of leukemia stem cells (LSCs). Here, we report that an unappreciated RNA-binding protein, Rbm5, selectively promotes murine leukemogenesis, maintains LSC self-renewal in vivo, and is dispensable for normal hematopoiesis. Rbm5 is highly expressed in LSCs, and its deficiency results in specifically defective LSC function, along with inhibition of self-renewal gene expression and induction of myeloid differentiation. Multi-disciplinary mechanistic investigations further identified Myc as the major and direct transcriptional target of Rbm5 in primary leukemia cells. Moreover, RBM5 not only interacts with MYC but also maintains its protein levels, thereby sustaining the Myc downstream transcriptional network through its proper genome-wide occupancy. Forced expression of Myc sufficiently rescued the Rbm5-depleted LSC defects. Thus, our study demonstrates that Rbm5 regulates the AML LSC program through non-canonical transcriptional mechanisms, providing a strong rationale for targeting Rbm5 therapeutically. In Brief. Zhang et al. illustrate the role of Rbm5 in sustaining the self-renewal program in leukemia stem. cells (LSCs) primarily through the Myc transcriptional network. Specifically, Rbm5 loss results in a significant decrease in Myc protein levels, thereby disrupting. the Myc downstream transcriptional network in LSCs. Notably, this effect is specific to LSCs, as. normal hematopoietic stem cells (HSCs) do not exhibit such changes upon Rbm5 loss.
The study depicts an epigenetic polarity governing Treg-mediated immune tolerance, highlighting a fundamental asymmetry at the epigenetic level that differentially regulates Treg and conventional T cells.
Wenjun Huang, Yongqiang Feng, Jun Li et al.· Journal of Immunology· 0 citations