Exploiting molecular diversity to interrogate T cell recognition and specificities in cancer
Abstract/Contents
- Abstract
- Applying protein engineering to immunological problems can provide insight into understanding the targeted nature of the T cell immune response. T cells have specificity through their T cell receptor for peptides presented by proteins called Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) in humans. This interaction is critical for the immune response to protect the host from foreign pathogens and cancer. By engineering peptide-MHC/HLA libraries for yeast-display, we can mimic the presentation of nearly 1 billion different antigens to 1) survey properties of TCR recognition and 2) identify peptide ligands. We have applied this technology in several capacities -- 1) to uncover general properties of TCR recognition at extremely low affinities by developing a novel peptide 'velcro' that raises the apparent affinity of an interaction in a peptide-dependent manner and 2) to couple the platform with novel statistical algorithms to predict the specificities of TCRs and potential off-target specificities of TCRs with known and unknown specificities, especially those derived from tumor-infiltrating lymphocytes. In application 1, we have uncovered that general principles of TCR cross-reactivity are maintained at extremely low affinities (Kd > 100 μM) as they are at normal affinities (Kd ~ 1-100 μM). The implications of conserved cross-reactivities are important for understanding recognition in positive selection, T cell tonic signaling, and the relationship between specificity and affinity of protein-protein interactions. In application 2, we are pioneering an important technology that provides an ability to directly determine the specificity of a TCR. We have validated the prediction algorithms by identifying the specificity and cross-reactivities of known TCRs and applied this to TCRs of unknown specificity isolated from tumor-infiltrating lymphocytes. We have identified a shared non-mutated target of the immune system in 2/2 colorectal adenocarcinoma patients. Approaches used here can expand the pool of knowledge in T cell biology, receptor specificity, and immune responses in cancer or other T-cell mediated diseases.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Gee, Marvin Ho-Yan |
|---|---|
| Associated with | Stanford University, Program in Immunology. |
| Primary advisor | Garcia, K. Christopher |
| Thesis advisor | Garcia, K. Christopher |
| Thesis advisor | Boyd, Scott, 1970- |
| Thesis advisor | Davis, Mark M |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Quake, Stephen Ronald |
| Advisor | Boyd, Scott, 1970- |
| Advisor | Davis, Mark M |
| Advisor | Engleman, Edgar G |
| Advisor | Quake, Stephen Ronald |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Marvin Ho-Yan Gee. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Marvin Ho-Yan Gee
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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