Tissue mechanics control T cell activation and metabolism through YAP
Abstract/Contents
- Abstract
- T cells encounter forces at the tissue scale as they traverse through a variety of microenvironmental mechanical contexts, including sites of infection, inflammation, and cancer. The transcriptional coactivator Yes-associated protein (YAP) is a well-known sensor of tissue mechanics that is dominantly regulated by the stiffness of extracellular matrix. Understanding microenvironmental mechanosensing has offered revolutionary leaps in the fields of cellular development, organ size regulation, stem cell differentiation, cancer metastasis, and programmed cell death. The role of YAP has been well established in cancer metastasis and recent works have implicated YAP in immunity, but there have been no links yet between YAP and mechanics in immune cells, and environmental mechanosensing has never been demonstrated for T cells. To shed light on T cell pathophysiology in disease-associated tissues, this dissertation sought to determine how mechanical signals translate to regulation of the T cell effector and metabolic program through YAP. We describe a conditional knockout mouse model to analyze the effects of YAP on T cell activation and metabolism. We discover YAP to be an unexpected suppressor of T cell activation and metabolic reprogramming and demonstrate that this inhibition extends to in vivo T cell responses to infection and autoimmunity. We report a mechanism of YAP-mediated suppression of T cell proliferation and metabolism. Finally, we address a long-standing question of how T cells respond to tissue mechanics using biomimetic matrices and identify YAP as a key player in T cell mechanotransduction. In summary, this dissertation reveals a new paradigm whereby tissue mechanics fine-tunes adaptive immune responses in health and disease. Our work sets a foundation for the exciting therapeutic potential of either inhibiting YAP to promote T cell response while simultaneously impairing tumor growth, or conversely inducing YAP activity to relieve T cell-dependent autoimmune disease and blood cancers. Altogether, we highlight the importance of future ventures toward understanding how T cells respond to their mechanical microenvironment.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Meng, Kevin |
|---|---|
| Degree supervisor | Bollyky, Paul |
| Degree supervisor | Butte, M. (Manish) |
| Thesis advisor | Bollyky, Paul |
| Thesis advisor | Butte, M. (Manish) |
| Thesis advisor | Davis, Mark M |
| Thesis advisor | Idoyaga, Juliana |
| Thesis advisor | Sage, Julien |
| Degree committee member | Davis, Mark M |
| Degree committee member | Idoyaga, Juliana |
| Degree committee member | Sage, Julien |
| Associated with | Stanford University, Department of Microbiology and Immunology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Kevin P. Meng. |
|---|---|
| Note | Submitted to the Department of Microbiology and Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Kevin Meng
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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