Modulation of regulatory T cell function by tissue extracellular matrix
Abstract/Contents
- Abstract
- Regulatory T lymphocytes are an essential component of the immune system -- in their absence, autoimmunity develops. Maintenance of regulatory T cells is thought to rely predominately on the transcription factor Foxp3, IL-2 signaling and T cell receptor stimulation. While these three factors are essential for regulatory T cell function, interactions with the tissues may also play a critical role in their function and persistence. To carry out their nonredundant role in immune suppression, these T cells must navigate the extracellular matrix -- the cellular environment composed of proteins, proteoglycans, and glycosaminoglycans. Our current understanding of regulatory T cells does not fully account for how the matrix interacts with and contributes to regulatory T cell function. To better understand this relationship, we examined two extracellular matrix glycopolymers, hyaluronan and heparan sulfate, and their respective receptors, CD44 and heparanase. We investigated the role of these polymers and receptors in regulatory T cell stability, function, and persistence. Hyaluronan is a glycosaminoglycan composed of repeating disaccharides subunits, N-acetyl glucosamine, and D-glucuronic acid. Hyaluronan is abundant in tissues, with elevated expression during inflammation. CD44 is an alternatively spliced glycoprotein that serves as the cognate receptor for hyaluronan and is ubiquitously expressed on hematopoietic cells. Herein we examined the function of hyaluronan CD44 interactions on primary mouse and human CD4+ regulatory T cells. Engagement of CD44 with hyaluronan or overexpressing CD44, improves regulatory T cell activation and increases regulatory T cell suppression. Heparan sulfate is another glycosaminoglycan abundant within the matrix but differs from hyaluronan in that heparan sulfate is covalently linked to a protein backbone. Heparan sulfate itself is known to bind many diverse protein ligands and modulate ligand-receptor signaling. Heparanase is an enzyme that binds and cleaves heparan sulfate polymers. The cytokine interleukin 2 exhibits heparan sulfate binding, yet little is known about its contribution to regulatory T lymphocyte biology. We discovered the role for heparan sulfate interleukin 2 complexes and heparanase in modulating regulatory T lymphocyte function. Specifically, we found that heparan sulfate interleukin 2 complexes exert increased signaling agonism compared to interleukin 2 alone. Additionally, heparanase is required for optimal regulatory T lymphocyte function and survival; without it, mice undergoing experimental autoimmune encephalomyelitis exhibit worse disease. This thesis provides evidence that the ECM components hyaluronan, heparan sulfate, and their respective receptors contribute to regulatory T cell homeostasis. Future work in understanding autoimmunity and associated therapeutics needs to consider the role of the extracellular matrix in regulatory T cell fate.
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 | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Martinez, Hunter Antonio |
|---|---|
| Degree supervisor | Bollyky, Paul |
| Thesis advisor | Bollyky, Paul |
| Thesis advisor | Jagannathan, Prasanna |
| Thesis advisor | Maltzman, Jonathan |
| Thesis advisor | Meyer, Everett |
| Degree committee member | Jagannathan, Prasanna |
| Degree committee member | Maltzman, Jonathan |
| Degree committee member | Meyer, Everett |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Program in Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Hunter A. Martinez. |
|---|---|
| Note | Submitted to the Graduate Program of Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/zm447nw4770 |
Access conditions
- Copyright
- © 2023 by Hunter Antonio Martinez
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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