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-beta signaling, was preferentially translated in TCR-activated T-REG cells compared with conventional, murine CD4(+) T cells. TGF-beta 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-beta 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-beta 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-beta 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-beta-dependent differentiation of T-EFF cells to peripherally induced T-REG and T(H)17 cells.