The Deubiquitinating Enzyme Ubiquitin-Specific Peptidase 11 Potentiates TGF-β Signaling in CD4+ T Cells to Facilitate Foxp3+ Regulatory T and TH17 Cell Differentiation

Foxp3⁺ regulatory T (T_REG) cells are central mediators in the control of peripheral immune responses. Genome-wide transcriptional profiles show canonical signatures for Foxp3⁺ T_REG cells, distinguishing them from Foxp3^- effector T (T_EFF) cells. We previously uncovered distinct mRNA translational signatures differentiating CD4⁺ T_EFF and T_REG cells through parallel measurements of cytosolic (global) and polysome-associated (translationally enhanced) mRNA levels in both subsets. We show that the mRNA encoding for the ubiquitin-specific peptidase 11 (USP11), a known modulator of TGF-β signaling, was preferentially translated in TCR-activated T_REG cells compared with conventional, murine CD4⁺ T cells. TGF-β is a key cytokine driving the induction and maintenance of Foxp3 expression in T cells. We hypothesized that differential translation of USP11 mRNA endows T_REG cells with an advantage to respond to TGF-β signals. In an in vivo mouse model promoting T_REG cells plasticity, we found that USP11 protein was expressed at elevated levels in stable T_REG cells, whereas ectopic USP11 expression enhanced the suppressive capacity and lineage commitment of these cells in vitro and in vivo. USP11 overexpression in T_EFF cells enhanced the activation of the TGF-β pathway and promoted T_REG or T_H17, but not Th1, cell differentiation in vitro and in vivo, an effect abrogated by USP11 gene silencing or the inhibition of enzymatic activity. Thus, USP11 potentiates TGF-β signaling in both T_REG and T_EFF cells, in turn driving increased suppressive function and lineage commitment in thymic-derived T_REG cells and potentiating the TGF-β-dependent differentiation of T_EFF cells to peripherally induced T_REG and T_H17 cells.