The Deubiquitinating Enzyme Ubiquitin-Specific Peptidase 11 Potentiates TGF-β Signaling in CD4 T Cells to Facilitate Foxp3 Regulatory T and T17 Cell Differentiation.

Foxp3 regulatory T (T) cells are central mediators in the control of peripheral immune responses. Genome-wide transcriptional profiles show canonical signatures for Foxp3 T cells, distinguishing them from Foxp3 effector T (T) cells. We previously uncovered distinct mRNA translational signatures differentiating CD4 T and T 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 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 cells with an advantage to respond to TGF-β signals. In an in vivo mouse model promoting T cells plasticity, we found that USP11 protein was expressed at elevated levels in stable T cells, whereas ectopic USP11 expression enhanced the suppressive capacity and lineage commitment of these cells in vitro and in vivo. USP11 overexpression in T cells enhanced the activation of the TGF-β pathway and promoted T or T17, 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 and T cells, in turn driving increased suppressive function and lineage commitment in thymic-derived T cells and potentiating the TGF-β-dependent differentiation of T cells to peripherally induced T and T17 cells.