Thesis
Genomic analyses of the immune system
- Abstract:
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Project 1. Genetic variation in key immune system components
Genes underpinning the diversity and plasticity of the human adaptive immune system, such as the HLA and immunoglobulins, are known for their complex structures and polymorphism. The emergence of long-read sequencing technologies has revolutionised genomics research, in particular the characterisation of segmental duplications and structural variation. Here, using long-read sequencing and additional genomics data from a healthy donor identified as HV31, I built two iterations of de novo personal genome assemblies for HV31 as a foundation to study the genetic variation of the immune system. I analysed complex structural variants found in genomic regions encoding key immune system components, and validated them against sequencing data. I also evaluated long-read sequencing accuracy and developed a tool for genomic data visualisation. Collectively, these efforts demonstrate the applications of personal genome assemblies in studying the immune system.
Project 2. Effects of low-dose IL-2 immunotherapy in T and NK cells
Low-dose interleukin-2 (IL-2) immunotherapy is a promising treatment for type 1 diabetes (T1D). IL-2 supresses autoimmune reactions by increasing the number of regulatory T cells (Tregs). To better understand the mechanism of action of low- dose IL-2 immunotherapy, I analysed single-cell multiomics data of T and NK cells collected from T1D patients before and after low-dose IL-2 treatment. I confirmed that low-dose IL-2 selectively expanded thymic-derived FOXP3+ HELIOS+ regulatory T cells and CD56br NK cells, and showed that the treatment reduced the frequency of IL-21-producing CD4+ T cells. In addition, I identified a long-lived gene expression signature induced by IL-2, which featured the upregulation of CISH and downregulation of AREG. Notably, I found that the signature remained detectable one month after the treatment. Further analyses of publicly available COVID-19 cohort data revealed that SARS-CoV-2 infection induced opposite changes that persisted for several months after recovery. These findings suggested potential mechanisms of long COVID and longer-term benefits of IL-2 immunotherapy.
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(Preview, Dissemination version, pdf, 33.8MB, Terms of use)
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Authors
Contributors
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- Human Genetics Wt Centre
- Research group:
- JDRF/Wellcome Diabetes and Inflammation Laboratory (DIL)
- Oxford college:
- Brasenose College
- Role:
- Supervisor
- ORCID:
- 0000-0003-2740-8148
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- Human Genetics Wt Centre
- Role:
- Supervisor
- ORCID:
- 0000-0002-1710-9024
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- Human Genetics Wt Centre
- Research group:
- JDRF/Wellcome Diabetes and Inflammation Laboratory (DIL)
- Role:
- Supervisor
- ORCID:
- 0000-0001-5733-3285
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- Human Genetics Wt Centre
- Research group:
- JDRF/Wellcome Diabetes and Inflammation Laboratory (DIL)
- Role:
- Supervisor
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Biochemistry
- Role:
- Supervisor
- Programme:
- China Scholarship Council-University of Oxford Scholarship
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
-
English
- Keywords:
- Subjects:
- Pubs id:
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2043185
- Local pid:
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pubs:2043185
- Deposit date:
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2023-10-11
- ARK identifier:
Terms of use
- Copyright holder:
- Zhang, J
- Copyright date:
- 2023
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