Lack of phospho-eIF4E worsens experimental colitis by inhibiting Treg suppressive activity.

[BACKGROUND] Phosphorylation of eIF4E by MNK1/2 modulates protein synthesis by controlling the translation of specific mRNAs. Immune cells use the MNK1/2-eIF4E axis to adapt their gene expression in response to environmental cues, but its dysregulated activity promotes disease progression. While recent examples using cancer models have identified CD8 T-cells as a conduit for the tumor-supporting role of the MNK1/2-eIF4E axis, the impact of phospho-eIF4E on CD4 T-cell subsets, specifically regulatory T-cells, remains unclear. To fill this knowledge gap, we studied the impact of phospho-eIF4E-deficiency on Treg activity in mice in an inflammatory context using a model of murine colitis and in human PBMCs.

[RESULTS] We found that Tregs isolated from mice deficient for phospho-eIF4E (expressing a serine-to-alanine mutation at S209) had a diminished ability to control CD4 T-cell proliferation and IFNγ secretion in vitro. We further report aggravated colitis in mice deficient in phospho-eIF4E accompanied by an increase in CD4 T-cells expressing IFNγ and a reduction in Tregs in the mesenteric lymph nodes and colon. Mechanistically, T-cells lacking phospho-eIF4E show impaired differentiation into Tregs, and Tregs lacking phospho-eIF4E have reduced FoxP3 expression and diminished migration to the lymph nodes. Using human PBMCs, anti-CTLA-4, but not anti-PD-1, reduced the phospho-eIF4E-expressing Treg population.

[CONCLUSIONS] Taken together, these data highlight a role for phospho-eIF4E in Treg biology and in the control of inflammation.

[CLINICAL TRIAL NUMBER] Not applicable.