University of Cambridge
Understanding the role of CD4+ T cells in common immune-mediated diseases
Abstract
dc:description.abstractImmune-mediated diseases such as autoimmunity are complex traits which collectively affect around 10% of the European population. Genome-wide association studies (GWAS) have demonstrated that genetic susceptibility to these diseases is explained by thousands of loci spread throughout the genome, most of which lie within non-coding DNA. Moreover, these loci are enriched in CD4+ T cell regulatory elements, which suggests they might disrupt the expression of nearby genes in T cells. Nonetheless, the target genes of most immune disease loci have yet to be discovered. In this dissertation, I describe three studies designed to further our understanding of the relationship between genetic variation, CD4+ T cell function, and disease risk. I first introduce a large epigenetic study which profiled active promoters and enhancers in 55 different CD4+ T cell and macrophage states. By integrating these data with GWAS loci with a novel statistical approach, I conclude that immune disease loci are enriched in enhancers and promoters specifically active during early memory T cell activation. In a second study, I proceed to characterize memory CD4+ T cells at single-cell resolution by profiling cells in the resting state and after stimulation with 11 different cytokine combinations. My observations reveal that CD4+ T cells are formed of a continuum of cell states which reflect a naïve-to-memory progression, and that as cells advance in this progression they express increasingly higher levels of cytokines, chemokines, and other effector molecules. Finally, I describe the results from a single-cell expression quantitative trait locus (sc-eQTL) mapping study performed on CD4+ T cells undergoing activation. I identify over 6,000 genes regulated by an eQTL, of which approximately 2,000 show evidence of a gene-by-environment interaction, where the eQTL effect size changes as a function of T cell activation time. Integration with GWAS associations demonstrates that immune disease loci alter the expression of genes in cis at specific stages of T cell activation. This results in the prioritization of 139 candidate disease genes which could be relevant for drug target identification. These results expand our understanding of CD4+ T cells and suggest that dysregulation of gene expression dynamics during T cell activation could be a hallmark of disease.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2021
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Cano Gamez, Eddie
- Advisor dc:contributor.advisor
-
- Trynka, Gosia
Subjects
dc:subject × 6Rights
dc:rightsIdentifiers
dc:identifier.*- Author Identifier
- 0000-0003-2753-1226
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/323427