Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8⁺T cell

Abstract

During the primary response, the commitment of the CD8 + T cell to Blimp-1 expression and the terminal differentiation that Blimp-1 induces must be timed so as not to impair the process of clonal expansion. We determined whether the Hippo pathway, which links cell–cell contact to differentiation in other cell lineages, controls Blimp-1 expression. Activating the CD8 + T cell with antigen and IL-2 causes expression of the core Hippo pathway components, including the pivotal transcriptional cofactor Yap. Contact between activated CD8 + T cells induces Hippo pathway-mediated Yap degradation and Blimp-1 expression; a Hippo-resistant, stable form of Yap suppresses Blimp-1 expression. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and CD80 comprise the receptor–ligand pair that mediates contact-dependent Hippo pathway activation. In vivo, CD8 + T cells expressing Hippo resistant-Yap or lacking CTLA-4 have diminished expression of the senescence marker, KLRG1, during a viral infection. The CTLA-4/Hippo pathway/Blimp-1 system may couple terminal differentiation of CD8 + T cell with the magnitude of clonal expansion.

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

“…This process, termed quorum sensing, allows individual members of a community to exhibit collectivist behaviors in order to coordinate expression of energetically expensive processes involved in virulence and differentiation (71). While quorum sensing has been theorized to be relevant to understanding lymphocyte behavior (72,73), our data add to growing experimental data demonstrating that, under certain circumstances, T cells can also exhibit collectivist behaviors (74,75).…”

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 + T cells

“…6B), suggesting that depleting FAP + FRCs during the late phase of the immune response results in increased terminal differentiation of virus-specific CD8 + T cells. This finding may reflect an increased frequency of contact between activated cells, secondary to the loss of naïve T cells, which triggers the Hippo pathway and induces the expression of Blimp-1 (29).…”

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…The transcription factor TCF-7 also known as T-cell factor 1 functions downstream of WNT-b-catenin pathway and enhances memory formation at least partially by induction of Eomes (Jeannet et al 2010;Zhou et al 2010). Furthermore, effector Tc1 differentiation is enhanced by the Hippo pathway, which is activated by cell-cell contact signals via CTLA4 and its ligand CD80, probably by suppression of Eomes and induction of Blimp-1 (Thaventhiran et al 2012).…”