In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 33 ( 2012-08-14)
Abstract:
The finding that the Hippo pathway links the expression of Blimp-1 , a gene that mediates differentiation, to the population density of activated CD8 + T cells provides a mechanism to account for the ability of the antigen-specific population to sense when adequate expansion has occurred, and it is reminiscent of quorum sensing in bacteria and yeast. In the early phase of the immune response, replication will drive clonal expansion, because the low frequency of antigen-specific CD8 + T cells makes contact between them improbable. Only when replication has vastly increased their numbers will contact between activated cells and triggering of the Hippo pathway through the CTLA-4/CD80 receptor–ligand pair occur, creating a steady state where the rates of differentiation and replication are balanced ( Fig. P1 ). It is also noteworthy that CTLA-4, a receptor that has been of great interest because of its essential role in regulating autoimmunity, mediates the contact-dependent activation of the Hippo pathway and lymphocyte differentiation. We then showed that CTLA-4 and the Hippo pathway regulate terminal differentiation of the CD8 + T cell in vivo by adoptively transferring to mice virus-specific CD8 + T cells, in which Hippo pathway activation would be prevented by the absence of CTLA-4 or the presence of a Hippo-resistant form of Yap. Recipient mice were challenged by infection with a murine γ-herpesvirus-68. At the peak of the immune response to the virus, the transferred virus-specific cells maintained a less differentiated phenotype with respect to their relative expression of killer cell lectin-like receptor G1 (KLRG1) and CD127. The cell lineage-specific receptor–ligand pairs that mediate activation of the Hippo pathway in the various mammalian cell types, in which this pathway has a developmental role, have been difficult to identify. We were able to identify them by blocking CD80, which is up-regulated on the activated T cell, thereby preventing activation of the Hippo pathway and Blimp-1 expression. CD80 can engage cytotoxic T lymphocyte antigen 4 (CTLA-4) or CD28. Because agonistic antibody to CTLA-4 but not antibody to CD28 triggered the Hippo pathway, CTLA-4 and CD80 were identified as the receptor–ligand pair. The likelihood that CTLA-4 may be the only lymphocyte receptor that triggers the Hippo pathway was supported by the finding that Yap was stable in activated T cells in mice deficient for CTLA-4. We found here that the Hippo pathway was not constitutively active in CD8 + T cells but assembled in response to the signals necessary for terminal differentiation, antigen, and IL-2. Contact between activated CD8 + T cells triggered the Hippo pathway, leading to phosphorylation and degradation of Yap and expression of Blimp-1. The role of the Hippo pathway in regulating Blimp-1 was also shown by the ability of a nonphosphorylated form of Yap to suppress expression of Blimp-1 by contacting activated CD8 + T cells. The commitment of CD8 + T cells to terminal differentiation can be linked to the magnitude of clonal expansion if activated cells were able to detect each other among the larger population of nonactivated T cells. A cell–cell contact system that regulates organ size in metazoans is the Hippo pathway ( 3 ). This pathway is triggered when a ligand on one cell interacts with a receptor on the adjacent cell and leads to the phosphorylation of the transcriptional cofactor Yap to cause its sequestration in the cytoplasm, ubiquitination, and degradation. Using an in vitro culture system in which nonredundant requirements for signaling could be defined, we sought to identify the necessary signals for assembly and activation of the Hippo pathway and show its effects on Blimp-1 expression. On infection, rare antigen-specific CD8 + T-cell clones rapidly replicate to generate large numbers of differentiated effector cells that will ultimately control infection. Because terminally differentiated cells become senescent, replicating antigen-specific CD8 + T cells must commit to terminal differentiation at the appropriate time. If too early, the number of replicating cells will be small and will generate few fully differentiated effector cells. If inappropriately delayed, infection may overwhelm the host. The transcription factor Blimp-1 mediates terminal differentiation ( 1 , 2 ), but the appropriate timing of its expression is unknown. We propose here a possible answer by showing that the Hippo pathway of organ size control regulates the expression of Blimp-1 by the CD8 + T cell.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1209115109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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