Category: Immunity & infection

We have shown that distinct mRNA translational signatures distinguish Foxp3+ regulatory (T_REG) from conventional CD4⁺ effector T (T_EFF) cells through genome-wide analysis of cytosolic and polyribosome-associated mRNA levels in CD4⁺ T cell subsets. mRNA encoding Ubiquitin Specific Peptidase 11 (USP11) was preferentially translated in TCR-activated T_REG cells. USP11 is known to modulate TGF-β signals but its function in T cells remains uncharacterized. Given the preferential translation of USP11 in T_REG cells and the importance of TGF-β in T_REG cell development, we examined whether this differential translation of USP11 mRNA could affect T_REG cell differentiation and function. Herein, we employ viral transduction to ectopically express or knock down USP11 in primary CD4⁺ T cells, along with pharmacologic inhibition of USP11 to determine how altered USP11 expression affects CD4⁺ T cell subset differentiation, lineage commitment and function. In a lymphopenia model, USP11 expression correlated with T_REG cells that maintained Foxp3 expression and kept a T_REG phenotype. Ectopic USP11 expression in T_REG cells in vitro enhanced lineage commitment and suppressive function. Additionally, ectopic USP11 expression in T_EFF cells facilitated TGF-β signalling. This led to enhanced Foxp3 induction both in vitro and in vivo. Conversely, shRNA knockdown of USP11 reduced Foxp3 induction both in vitro and in vivo.  Furthermore, ectopic USP11 expression in T_EFF cells drove T_H17 differentiation in polarizing conditions whereas inhibition of USP11 enzymatic activity reduced Th17 differentiation and Foxp3 induction in vitro. In conclusion, we identified a novel mechanism regulating the T_REG and Th17 differentiation axis in CD4⁺ T cells.

Presenting Author(s)

• RI

  Roman Istomine

  – Ph.D. Candidate, McGill University

Co-Author(s)

• FA

  Fernando Alvarez

  – Ph.D. Candidate, McGill University
• CP

  Ciriaco Piccirillo

  – Professor, McGill University