title: 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.
authors: Department of Immunology, Division of Infection and Immunity, University College London,  Royal Free Hospital, London NW3 2QG,  United Kingdom.
authors: James E D
authors: JE
authors: Thaventhiran
authors: Anja
authors: A
authors: Hoffmann
authors: Lukasz
authors: L
authors: Magiera
authors: Maike
authors: M
authors: de la Roche
authors: Holger
authors: H
authors: Lingel
authors: Monika
authors: M
authors: Brunner-Weinzierl
authors: Douglas T
authors: DT
authors: Fearon
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D008024:Ligands; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017346:Protein Serine-Threonine Kinases