{"id":{"repo_id":"soton","oai_identifier":"oai:eprints.soton.ac.uk:196563"},"canonical_url":"https://search.dev.ndltd.org/etd/soton/oai:eprints.soton.ac.uk:196563","repository":{"repo_id":"soton","name":"University of Southampton","base_url":"https://eprints.soton.ac.uk/cgi/oai2"},"display":{"title":"Functional analysis of TL1A/DR3 interactions during T cell-mediated immune responses","abstract":"Members of the tumour necrosis factor superfamily (TNFSF) are important regulators of inflammation and immunity. TL1A (TNFSF15), ligand for death receptor 3 (DR3), is the most recently discovered member of this superfamily and full understanding of its structure and the role in T cell-mediated immune responses is currently incomplete. DR3 expression is strongly up-regulated on activated T cells, although it also is present on resting CD4+ T cells, while the expression of TL1A is rapidly and transiently upregulated on activated cells of the immune system such as dendritic cells, monocytes and T cells. The research published to date shows that TL1A/DR3 interaction is involved in the pathogenesis of several autoimmune diseases and enhances activation of CD4+ T cells, however very little is known about its role in co-stimulation of CD8+ T cells. Several studies showed that TL1A also acts as a polarizer of the immune response by inducing secretion of IFN-?, IL-4, IL-10 and/or IL-17A from activated CD4+ T cells, although the results vary depending on the conditions of a given experiment. The research presented in this thesis identifies Toll-like receptors 3 and 4 as the inducers of TL1A expression on dendritic cells. Furthermore, different binding patterns of anti- TL1A monoclonal antibody (raised against the homotrimeric form of TL1A) and DR3.Fc construct to cells transfected with TL1A cDNA and cells naturally expressing TL1A suggest that TL1A may exist as a homo- and heterotrimeric protein. Ecotopic expression of TL1A on J558L tumour cells promotes their elimination in a CD8+ T celldependent manner and renders mice immune to a subsequent challenge with tumour cells. Moreover, TL1A promotes the proliferation and accumulation of antigen-specific CD8+ T cells both in vitro and in vivo as well as their activation and differentiation into cytotoxic T cells in vivo. It also enhances the secondary expansion of endogenous antigen-specific memory CD8+ T cells. The studies presented here also show that TL1A/DR3 interaction enhances the proliferation and activation of CD4+ T cells. CD11c-TL1A transgenic and CD2-TL1A transgenic mice that constitutively express TL1A on dendritic cells and T cells, respectively, show elevated levels of IL-13 and IL- 17A in the secondary lymphoid organs suggesting that in this setting TL1A skews the immune response toward Th2 and Th17 type. Furthermore, CD11c-TL1A transgenic mice develop a striking goblet cell hyperplasia in the ileum. TL1A also enhances regulatory T cell accumulation in vivo. The findings presented in this thesis show that TL1A may have the potential for enhancing vaccines that aim to elicit CD8+ T cell responses and also identify mechanisms by which sustained expression of TL1A could promote pathogenesis in inflammatory bowel disease","abstract_html":"Members of the tumour necrosis factor superfamily (TNFSF) are important regulators of inflammation and immunity. TL1A (TNFSF15), ligand for death receptor 3 (DR3), is the most recently discovered member of this superfamily and full understanding of its structure and the role in T cell-mediated immune responses is currently incomplete. DR3 expression is strongly up-regulated on activated T cells, although it also is present on resting CD4+ T cells, while the expression of TL1A is rapidly and transiently upregulated on activated cells of the immune system such as dendritic cells, monocytes and T cells. The research published to date shows that TL1A/DR3 interaction is involved in the pathogenesis of several autoimmune diseases and enhances activation of CD4+ T cells, however very little is known about its role in co-stimulation of CD8+ T cells. Several studies showed that TL1A also acts as a polarizer of the immune response by inducing secretion of IFN-?, IL-4, IL-10 and/or IL-17A from activated CD4+ T cells, although the results vary depending on the conditions of a given experiment. The research presented in this thesis identifies Toll-like receptors 3 and 4 as the inducers of TL1A expression on dendritic cells. Furthermore, different binding patterns of anti- TL1A monoclonal antibody (raised against the homotrimeric form of TL1A) and DR3.Fc construct to cells transfected with TL1A cDNA and cells naturally expressing TL1A suggest that TL1A may exist as a homo- and heterotrimeric protein. Ecotopic expression of TL1A on J558L tumour cells promotes their elimination in a CD8+ T celldependent manner and renders mice immune to a subsequent challenge with tumour cells. Moreover, TL1A promotes the proliferation and accumulation of antigen-specific CD8+ T cells both in vitro and in vivo as well as their activation and differentiation into cytotoxic T cells in vivo. It also enhances the secondary expansion of endogenous antigen-specific memory CD8+ T cells. The studies presented here also show that TL1A/DR3 interaction enhances the proliferation and activation of CD4+ T cells. CD11c-TL1A transgenic and CD2-TL1A transgenic mice that constitutively express TL1A on dendritic cells and T cells, respectively, show elevated levels of IL-13 and IL- 17A in the secondary lymphoid organs suggesting that in this setting TL1A skews the immune response toward Th2 and Th17 type. Furthermore, CD11c-TL1A transgenic mice develop a striking goblet cell hyperplasia in the ileum. TL1A also enhances regulatory T cell accumulation in vivo. The findings presented in this thesis show that TL1A may have the potential for enhancing vaccines that aim to elicit CD8+ T cell responses and also identify mechanisms by which sustained expression of TL1A could promote pathogenesis in inflammatory bowel disease","abstract_has_math":false,"creators":["Ślebioda, Tomasz Jerzy"],"institution":"University of Southampton","degree_name":"Ph.D.","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Al-Shamkhani, Aymen"],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-06","date_published":"2011-06","updated_at":"2026-07-24T04:36:32Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Al-Shamkhani, Aymen"]},{"key":"dc:creator","label":"Author","values":["Ślebioda, Tomasz Jerzy"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-06"]},{"key":"dc:date.issued","label":"Date","values":["2011-06"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Cancer Sciences (pre 2018 reorg)","School of Medicine"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Southampton"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://eprints.soton.ac.uk/196563/"]},{"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":["Ph.D."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://eprints.soton.ac.uk/196563/1/PhD_Tomasz_Slebioda.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Members of the tumour necrosis factor superfamily (TNFSF) are important regulators of inflammation and immunity. TL1A (TNFSF15), ligand for death receptor 3 (DR3), is the most recently discovered member of this superfamily and full understanding of its structure and the role in T cell-mediated immune responses is currently incomplete. DR3 expression is strongly up-regulated on activated T cells, although it also is present on resting CD4+ T cells, while the expression of TL1A is rapidly and transiently upregulated on activated cells of the immune system such as dendritic cells, monocytes and T cells. The research published to date shows that TL1A/DR3 interaction is involved in the pathogenesis of several autoimmune diseases and enhances activation of CD4+ T cells, however very little is known about its role in co-stimulation of CD8+ T cells. Several studies showed that TL1A also acts as a polarizer of the immune response by inducing secretion of IFN-?, IL-4, IL-10 and/or IL-17A from activated CD4+ T cells, although the results vary depending on the conditions of a given experiment. The research presented in this thesis identifies Toll-like receptors 3 and 4 as the inducers of TL1A expression on dendritic cells. Furthermore, different binding patterns of anti- TL1A monoclonal antibody (raised against the homotrimeric form of TL1A) and DR3.Fc construct to cells transfected with TL1A cDNA and cells naturally expressing TL1A suggest that TL1A may exist as a homo- and heterotrimeric protein. Ecotopic expression of TL1A on J558L tumour cells promotes their elimination in a CD8+ T celldependent manner and renders mice immune to a subsequent challenge with tumour cells. Moreover, TL1A promotes the proliferation and accumulation of antigen-specific CD8+ T cells both in vitro and in vivo as well as their activation and differentiation into cytotoxic T cells in vivo. It also enhances the secondary expansion of endogenous antigen-specific memory CD8+ T cells. The studies presented here also show that TL1A/DR3 interaction enhances the proliferation and activation of CD4+ T cells. CD11c-TL1A transgenic and CD2-TL1A transgenic mice that constitutively express TL1A on dendritic cells and T cells, respectively, show elevated levels of IL-13 and IL- 17A in the secondary lymphoid organs suggesting that in this setting TL1A skews the immune response toward Th2 and Th17 type. Furthermore, CD11c-TL1A transgenic mice develop a striking goblet cell hyperplasia in the ileum. TL1A also enhances regulatory T cell accumulation in vivo. The findings presented in this thesis show that TL1A may have the potential for enhancing vaccines that aim to elicit CD8+ T cell responses and also identify mechanisms by which sustained expression of TL1A could promote pathogenesis in inflammatory bowel disease"]},{"key":"dc:format","label":"Dc Format","values":["text"]},{"key":"dc:title","label":"Title","values":["Functional analysis of TL1A/DR3 interactions during T cell-mediated immune responses"]}]}],"canonical_facts":{"dc:contributor.advisor":["Al-Shamkhani, Aymen"],"dc:creator":["Ślebioda, Tomasz Jerzy"],"dc:date":["2011-06"],"dc:date.issued":["2011-06"],"dc:description.abstract":["Members of the tumour necrosis factor superfamily (TNFSF) are important regulators of inflammation and immunity. TL1A (TNFSF15), ligand for death receptor 3 (DR3), is the most recently discovered member of this superfamily and full understanding of its structure and the role in T cell-mediated immune responses is currently incomplete. DR3 expression is strongly up-regulated on activated T cells, although it also is present on resting CD4+ T cells, while the expression of TL1A is rapidly and transiently upregulated on activated cells of the immune system such as dendritic cells, monocytes and T cells. The research published to date shows that TL1A/DR3 interaction is involved in the pathogenesis of several autoimmune diseases and enhances activation of CD4+ T cells, however very little is known about its role in co-stimulation of CD8+ T cells. Several studies showed that TL1A also acts as a polarizer of the immune response by inducing secretion of IFN-?, IL-4, IL-10 and/or IL-17A from activated CD4+ T cells, although the results vary depending on the conditions of a given experiment. The research presented in this thesis identifies Toll-like receptors 3 and 4 as the inducers of TL1A expression on dendritic cells. Furthermore, different binding patterns of anti- TL1A monoclonal antibody (raised against the homotrimeric form of TL1A) and DR3.Fc construct to cells transfected with TL1A cDNA and cells naturally expressing TL1A suggest that TL1A may exist as a homo- and heterotrimeric protein. Ecotopic expression of TL1A on J558L tumour cells promotes their elimination in a CD8+ T celldependent manner and renders mice immune to a subsequent challenge with tumour cells. Moreover, TL1A promotes the proliferation and accumulation of antigen-specific CD8+ T cells both in vitro and in vivo as well as their activation and differentiation into cytotoxic T cells in vivo. It also enhances the secondary expansion of endogenous antigen-specific memory CD8+ T cells. The studies presented here also show that TL1A/DR3 interaction enhances the proliferation and activation of CD4+ T cells. CD11c-TL1A transgenic and CD2-TL1A transgenic mice that constitutively express TL1A on dendritic cells and T cells, respectively, show elevated levels of IL-13 and IL- 17A in the secondary lymphoid organs suggesting that in this setting TL1A skews the immune response toward Th2 and Th17 type. Furthermore, CD11c-TL1A transgenic mice develop a striking goblet cell hyperplasia in the ileum. TL1A also enhances regulatory T cell accumulation in vivo. The findings presented in this thesis show that TL1A may have the potential for enhancing vaccines that aim to elicit CD8+ T cell responses and also identify mechanisms by which sustained expression of TL1A could promote pathogenesis in inflammatory bowel disease"],"dc:format":["text"],"dc:identifier.uri":["https://eprints.soton.ac.uk/196563/1/PhD_Tomasz_Slebioda.pdf"],"dc:publisher.department":["Cancer Sciences (pre 2018 reorg)","School of Medicine"],"dc:publisher.institution":["University of Southampton"],"dc:relation.isreferencedby":["https://eprints.soton.ac.uk/196563/"],"dc:title":["Functional analysis of TL1A/DR3 interactions during T cell-mediated immune responses"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["Ph.D."]},"updated_at":"2026-07-24T04:36:32Z"}