Abstract
Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 similar to 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.
Original language | English |
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Pages (from-to) | 1067-1082.e12 |
Number of pages | 28 |
Journal | Immunity |
Volume | 47 |
Issue number | 6 |
DOIs | |
Publication status | Published - 19-Dec-2017 |
Keywords
- COSTIMULATOR MESSENGER-RNA
- GERMINAL CENTER REACTION
- TH17 DIFFERENTIATION
- EFFECTOR LINEAGE
- ROR-GAMMA
- EXPRESSION
- MTOR
- AUTOIMMUNITY
- INFLAMMATION
- RECEPTOR