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 H 17, 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 H 17 cells.