CTLA-4 activates the hippo pathway to regulate terminal differentiation of the CD8+ T cell. (46.17)

Abstract

Abstract Replicating, antigen-specific CD8+ T cells must not commit to terminal differentiation until there has been sufficient clonal expansion. The Hippo pathway of organ size control mediates this requirement by linking expression of the differentiation-inducing transcription factor, Blimp-1, to contact between replicating cells, which would be dependent on their frequency. TCR and IL-2R stimulation assemble the Hippo pathway in the CD8+ T cell by inducing expression of WW45, Mob1, Lats1, and YAP, the transcriptional co-activator that mediates organ growth. Contact between activated CD8+ T cells triggers the Hippo pathway, causing serine phosphorylation and degradation of YAP. This is suppressed by addition of naïve CD8+ T cells, indicating that the ligand-receptor pair triggering the Hippo pathway is expressed only by activated cells. The ligand was identified by suppressing YAP degradation with blocking CD80/86 antibody, and the receptor was defined by inducing YAP degradation by crosslinking CTLA-4. That YAP regulates differentiation was shown by ectopically expressing a non-phosphorylatable, stable form of YAP in activated CD8+ T cells, which suppressed Blimp-1 expression in vitro, and the differentiation/senescence marker, KLRG1, in vivo. This role for CTLA-4 was confirmed by the presence of YAP in T cells from CTLA-4-/-, but not CTLA-4+/-, mice. Therefore, in a process that resembles quorum sensing, the Hippo pathway regulates terminal differentiation of the CD8+ T cell.