Protein Prenylation Drives Discrete Signaling Programs for the Differentiation and Maintenance of Effector T_reg Cells.

ABSTRACT: Effector regulatory T (eT_reg) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling mechanisms that promote the differentiation and maintenance of eT_reg cells remain unclear. Here, we show that isoprenoid-dependent posttranslational lipid modifications dictate eT_reg cell accumulation and function by intersecting with TCR-induced intracellular signaling. We find that isoprenoids are essential for activated T_reg cell suppressive activity, and T_reg cell-specific deletion of the respective farnesylation- and geranylgeranylation-promoting enzymes Fntb or Pggt1b leads to the development of fatal autoimmunity, associated with reduced eT_reg cell accumulation. Mechanistically, Fntb promotes eT_reg cell maintenance by regulating mTORC1 activity and ICOS expression. In contrast, Pggt1b acts as a rheostat of TCR-dependent transcriptional programming and Rac-mediated signaling for establishment of eT_reg cell differentiation and immune tolerance. Therefore, our results identify bidirectional metabolic signaling, specifically between immunoreceptor signaling and metabolism-mediated posttranslational lipid modifications, for the differentiation and maintenance of eT_reg cells.

SUBMITTER: Su W 

PROVIDER: S-EPMC7887758 | biostudies-literature |

REPOSITORIES: biostudies-literature