{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/323427"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/323427","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Understanding the role of CD4+ T cells in common immune-mediated diseases","abstract":"Immune-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.","abstract_html":"Immune-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.","abstract_has_math":false,"creators":["Cano Gamez, Eddie"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Trynka, Gosia"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-05","date_published":"2021-05","updated_at":"2026-07-22T22:24:03Z","subjects":["Immunology","Gene expression","Human genetics","Complex immune diseases","T cells","Immunogenomics"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b69f59c4-bba5-4851-b40e-cf7c13592410/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000327531226"],"render_values":[{"text":"0000-0003-2753-1226","href":"https://orcid.org/0000-0003-2753-1226","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.70885","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Trynka, Gosia"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Gates Cambridge Scholarship (Grant code: OPP1144) Open Targets (Grant code: OTAR040)"]},{"key":"dc:creator","label":"Author","values":["Cano Gamez, Eddie"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000327531226"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2021-05"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/323427"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Immunology","Gene expression","Human genetics","Complex immune diseases","T cells","Immunogenomics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b69f59c4-bba5-4851-b40e-cf7c13592410/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.70885"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/377a0c43-211e-4b8e-9e30-a751ad281713/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Immune-mediated diseases such as autoimmunity are complex traits which collectively affect around 10% of the European population. 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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. 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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. 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