Structure-based cytokine engineering
Abstract/Contents
- Abstract
- As a distributed network of cells, the immune system relies on secreted factors such as cytokines and chemokines to coordinate the induction and resolution of inflammation. Cytokine signaling is characterized by a high degree of pleiotropy in which a single cytokine acts on multiple cell types, often with countervailing effects. In many cases, this pleiotropy is critical for ensuring a robust immune response and maintaining tissue homeostasis but can present a problem for the clinical use of cytokines due to multiple responsive cell types. We applied the concept of partial agonism to two cytokines with different biological functions, interleukin 2 (IL-2) and IL-12. In the case of IL-2, we used a previously published structure of the complete IL-2 receptor complex to introduce mutations which attenuate binding to the common gamma chain and reduce receptor dimerization relative to wild-type IL-2. By profiling a diverse set of IL-2 partial agonists with reduced receptor dimerization, we identified a Treg biased agonist, IL-2-REH, which exploits two key features of Treg sensitivity to IL-2, constitutive expression of the IL-2 receptor alpha chain and reduced expression of Suppressor of Cytokine Signaling 1 (SOCS1), a negative regulator of IL-2 signaling. We sought to apply a similar concept to the heterodimeric cytokine IL-12, however, no structure of the IL-12 receptor complex was available. Using a combination of crystallography and cryo-electron microscopy, we solved structures of the IL-12 and closely related IL-23 receptor complexes. In both cases, the shared p40 subunit of IL-12/23 binds to the shared IL-12Rbeta1 receptor while unique four-helix bundles, IL-12p35 and IL-23p19, interact specifically with unique receptors, IL-12Rbeta2 and IL-23R. Guided by these structures, we generated IL-12 partial agonists with reduced binding to IL-12Rbeta1 which preserve T cell mediated anti-tumor immunity without NK cell induced toxicity relative to wild-type IL-12. Cytokine partial agonists present a path to translate structural understanding of cytokine receptor assembly to new molecules with distinct cell-type specific activity. Such agonists may have use clinically by enhancing efficacy, reducing toxicity, or both.
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 | 2021; ©2021 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Glassman, Caleb Randall |
|---|---|
| Degree supervisor | Garcia, K. Christopher |
| Thesis advisor | Garcia, K. Christopher |
| Thesis advisor | Bollyky, Paul |
| Thesis advisor | Ferrell, James Ellsworth |
| Thesis advisor | Jardetzky, Theodore |
| Degree committee member | Bollyky, Paul |
| Degree committee member | Ferrell, James Ellsworth |
| Degree committee member | Jardetzky, Theodore |
| Associated with | Stanford University, Program in Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Caleb Randall Glassman. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/gb066fk7861 |
Access conditions
- Copyright
- © 2021 by Caleb Randall Glassman
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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