{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/380644"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/380644","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Age-dependent changes in the mouse lymph node and implications for immune responses","abstract":"Older individuals tend to have an impaired production of antibodies after vaccination, however the cellular and molecular changes that cause this have not fully been elucidated. In this PhD project I aimed to investigate different aspects of the lymph node microenvironment to determine whether there are age-related alterations and if so, whether and how these might contribute to the diminished antibody production in aged individuals. The first step of an immune response in the lymph node starts with the entry of antigen to the tissue. Antigens enter the lymph node via lymphatic vessels either freely or carried by dendritic cells. I hypothesised that antigen access to the lymph node is impaired in ageing. To test this, I injected two sizes of nanoparticles, 20nm and 1000nm, enter the lymph node by free drainage in the lymph and carried in by immune cells, respectively. I observed that localisation of 20nm nanoparticles to the B cell follicle of the murine lymph node was impaired in 22-23 months old, aged mice. However, there are no significant changes to larger 1000nm particles that are typically delivered by dendritic cells to the lymph node with age. As the B cell follicle is the place where germinal centre develops, lack of access to antigen in the B cell follicle could be one of the factors that contribute to diminished germinal centre and antibody responses in ageing. Another key factor of the lymph node microenvironment is the lymph node stromal cells. Within the B cell follicle, mesenchyme-derived follicular dendritic cells network retains antigens for B cell access prior to and during the germinal centre response. With age, a failure to upregulate FcγRIIb has been reported in follicular dendritic cells. However, whether this is contributing to the age-related GC dysfunction remains unknown. I hypothesised that failed FcγRIIb upregulation on follicular dendritic cells during vaccination plays a contributory role in the impaired GC in aged mice. To test this hypothesis, I reconstituted FcγRIIb knock-in mice that have FcγRIIb upregulation defect upon immunisation on GC B cells with wild-type bone marrow, generating a chimeric model where any changes in FcγRIIb expression will be restricted to radiation resistant cells, which includes follicular dendritic cells. After immunisation, FcγRIIb knock-in chimeric mice had reduced antigen-specific IgG1 in their serum and fewer antigen-specific plasma cells in the bone marrow. These findings highlight v the role of FcγRIIb upregulation on follicular dendritic cells for robust antibody responses, and its compromised efficiency with ageing. Beyond the B cell follicle, the lymph node stromal cell network plays important role in regulating immune responses in the lymph node because it is the physical scaffold upon which immune cells migrate, and a source of chemokines and cytokines that direct immune cell movement. To identify other possible age dependent changes in lymph node cells, I conducted single-cell RNA sequencing on gp38+ CD31- lymph node stromal cells as well as lymphocytes, from adult and aged mice after immunisation. Employing a hypothesis-free approach, I examined age-dependent changes in cell population and identified some differentially expressed genes in adult and aged lymph node gp38+ CD31- stromal cells and lymphocyte compartments. Altogether, the results suggest defects in different aspects of the lymph node microenvironment that might contribute together to the age-associated decline in humoral immunity.","abstract_html":"Older individuals tend to have an impaired production of antibodies after vaccination, however the cellular and molecular changes that cause this have not fully been elucidated. In this PhD project I aimed to investigate different aspects of the lymph node microenvironment to determine whether there are age-related alterations and if so, whether and how these might contribute to the diminished antibody production in aged individuals. The first step of an immune response in the lymph node starts with the entry of antigen to the tissue. Antigens enter the lymph node via lymphatic vessels either freely or carried by dendritic cells. I hypothesised that antigen access to the lymph node is impaired in ageing. To test this, I injected two sizes of nanoparticles, 20nm and 1000nm, enter the lymph node by free drainage in the lymph and carried in by immune cells, respectively. I observed that localisation of 20nm nanoparticles to the B cell follicle of the murine lymph node was impaired in 22-23 months old, aged mice. However, there are no significant changes to larger 1000nm particles that are typically delivered by dendritic cells to the lymph node with age. As the B cell follicle is the place where germinal centre develops, lack of access to antigen in the B cell follicle could be one of the factors that contribute to diminished germinal centre and antibody responses in ageing. Another key factor of the lymph node microenvironment is the lymph node stromal cells. Within the B cell follicle, mesenchyme-derived follicular dendritic cells network retains antigens for B cell access prior to and during the germinal centre response. With age, a failure to upregulate FcγRIIb has been reported in follicular dendritic cells. However, whether this is contributing to the age-related GC dysfunction remains unknown. I hypothesised that failed FcγRIIb upregulation on follicular dendritic cells during vaccination plays a contributory role in the impaired GC in aged mice. To test this hypothesis, I reconstituted FcγRIIb knock-in mice that have FcγRIIb upregulation defect upon immunisation on GC B cells with wild-type bone marrow, generating a chimeric model where any changes in FcγRIIb expression will be restricted to radiation resistant cells, which includes follicular dendritic cells. After immunisation, FcγRIIb knock-in chimeric mice had reduced antigen-specific IgG1 in their serum and fewer antigen-specific plasma cells in the bone marrow. These findings highlight v the role of FcγRIIb upregulation on follicular dendritic cells for robust antibody responses, and its compromised efficiency with ageing. Beyond the B cell follicle, the lymph node stromal cell network plays important role in regulating immune responses in the lymph node because it is the physical scaffold upon which immune cells migrate, and a source of chemokines and cytokines that direct immune cell movement. To identify other possible age dependent changes in lymph node cells, I conducted single-cell RNA sequencing on gp38+ CD31- lymph node stromal cells as well as lymphocytes, from adult and aged mice after immunisation. Employing a hypothesis-free approach, I examined age-dependent changes in cell population and identified some differentially expressed genes in adult and aged lymph node gp38+ CD31- stromal cells and lymphocyte compartments. Altogether, the results suggest defects in different aspects of the lymph node microenvironment that might contribute together to the age-associated decline in humoral immunity.","abstract_has_math":false,"creators":["Ge, Xin"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Linterman, Michelle"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05-10","date_published":"2024-05-10","updated_at":"2026-07-22T22:24:04Z","subjects":["Ageing","Immune response","Lymph node","Immunosenescence"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f742c2b0-c802-4394-8e05-27a450230037/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.116209","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Linterman, Michelle"]},{"key":"dc:creator","label":"Author","values":["Ge, Xin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2024-05-10"]},{"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/1810/380644"]},{"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":["Ageing","Immune response","Lymph node","Immunosenescence"]}]},{"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/f742c2b0-c802-4394-8e05-27a450230037/download","http://purl.org/NET/rdflicense/allrightsreserved"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.116209"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/08e72d67-ad18-461d-94a0-185ca08b8954/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Older individuals tend to have an impaired production of antibodies after vaccination, however the cellular and molecular changes that cause this have not fully been elucidated. In this PhD project I aimed to investigate different aspects of the lymph node microenvironment to determine whether there are age-related alterations and if so, whether and how these might contribute to the diminished antibody production in aged individuals. The first step of an immune response in the lymph node starts with the entry of antigen to the tissue. Antigens enter the lymph node via lymphatic vessels either freely or carried by dendritic cells. I hypothesised that antigen access to the lymph node is impaired in ageing. To test this, I injected two sizes of nanoparticles, 20nm and 1000nm, enter the lymph node by free drainage in the lymph and carried in by immune cells, respectively. I observed that localisation of 20nm nanoparticles to the B cell follicle of the murine lymph node was impaired in 22-23 months old, aged mice. However, there are no significant changes to larger 1000nm particles that are typically delivered by dendritic cells to the lymph node with age. As the B cell follicle is the place where germinal centre develops, lack of access to antigen in the B cell follicle could be one of the factors that contribute to diminished germinal centre and antibody responses in ageing. Another key factor of the lymph node microenvironment is the lymph node stromal cells. Within the B cell follicle, mesenchyme-derived follicular dendritic cells network retains antigens for B cell access prior to and during the germinal centre response. With age, a failure to upregulate FcγRIIb has been reported in follicular dendritic cells. However, whether this is contributing to the age-related GC dysfunction remains unknown. I hypothesised that failed FcγRIIb upregulation on follicular dendritic cells during vaccination plays a contributory role in the impaired GC in aged mice. To test this hypothesis, I reconstituted FcγRIIb knock-in mice that have FcγRIIb upregulation defect upon immunisation on GC B cells with wild-type bone marrow, generating a chimeric model where any changes in FcγRIIb expression will be restricted to radiation resistant cells, which includes follicular dendritic cells. After immunisation, FcγRIIb knock-in chimeric mice had reduced antigen-specific IgG1 in their serum and fewer antigen-specific plasma cells in the bone marrow. These findings highlight v the role of FcγRIIb upregulation on follicular dendritic cells for robust antibody responses, and its compromised efficiency with ageing. Beyond the B cell follicle, the lymph node stromal cell network plays important role in regulating immune responses in the lymph node because it is the physical scaffold upon which immune cells migrate, and a source of chemokines and cytokines that direct immune cell movement. To identify other possible age dependent changes in lymph node cells, I conducted single-cell RNA sequencing on gp38+ CD31- lymph node stromal cells as well as lymphocytes, from adult and aged mice after immunisation. Employing a hypothesis-free approach, I examined age-dependent changes in cell population and identified some differentially expressed genes in adult and aged lymph node gp38+ CD31- stromal cells and lymphocyte compartments. 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In this PhD project I aimed to investigate different aspects of the lymph node microenvironment to determine whether there are age-related alterations and if so, whether and how these might contribute to the diminished antibody production in aged individuals. The first step of an immune response in the lymph node starts with the entry of antigen to the tissue. Antigens enter the lymph node via lymphatic vessels either freely or carried by dendritic cells. I hypothesised that antigen access to the lymph node is impaired in ageing. To test this, I injected two sizes of nanoparticles, 20nm and 1000nm, enter the lymph node by free drainage in the lymph and carried in by immune cells, respectively. I observed that localisation of 20nm nanoparticles to the B cell follicle of the murine lymph node was impaired in 22-23 months old, aged mice. However, there are no significant changes to larger 1000nm particles that are typically delivered by dendritic cells to the lymph node with age. As the B cell follicle is the place where germinal centre develops, lack of access to antigen in the B cell follicle could be one of the factors that contribute to diminished germinal centre and antibody responses in ageing. Another key factor of the lymph node microenvironment is the lymph node stromal cells. Within the B cell follicle, mesenchyme-derived follicular dendritic cells network retains antigens for B cell access prior to and during the germinal centre response. With age, a failure to upregulate FcγRIIb has been reported in follicular dendritic cells. However, whether this is contributing to the age-related GC dysfunction remains unknown. I hypothesised that failed FcγRIIb upregulation on follicular dendritic cells during vaccination plays a contributory role in the impaired GC in aged mice. To test this hypothesis, I reconstituted FcγRIIb knock-in mice that have FcγRIIb upregulation defect upon immunisation on GC B cells with wild-type bone marrow, generating a chimeric model where any changes in FcγRIIb expression will be restricted to radiation resistant cells, which includes follicular dendritic cells. After immunisation, FcγRIIb knock-in chimeric mice had reduced antigen-specific IgG1 in their serum and fewer antigen-specific plasma cells in the bone marrow. These findings highlight v the role of FcγRIIb upregulation on follicular dendritic cells for robust antibody responses, and its compromised efficiency with ageing. Beyond the B cell follicle, the lymph node stromal cell network plays important role in regulating immune responses in the lymph node because it is the physical scaffold upon which immune cells migrate, and a source of chemokines and cytokines that direct immune cell movement. To identify other possible age dependent changes in lymph node cells, I conducted single-cell RNA sequencing on gp38+ CD31- lymph node stromal cells as well as lymphocytes, from adult and aged mice after immunisation. Employing a hypothesis-free approach, I examined age-dependent changes in cell population and identified some differentially expressed genes in adult and aged lymph node gp38+ CD31- stromal cells and lymphocyte compartments. 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