{"id":{"repo_id":"umn","oai_identifier":"oai:conservancy.umn.edu:11299/218699"},"canonical_url":"https://search.dev.ndltd.org/etd/umn/oai:conservancy.umn.edu:11299/218699","repository":{"repo_id":"umn","name":"University of Minnesota","base_url":"https://conservancy.umn.edu/server/oai/request"},"display":{"title":"Programmed death-1 regulates islet-specific lymphocytes in type 1 diabetes","abstract":"Programmed death-1 (PD-1) is a T cell inhibitory receptor important for tolerance maintenance. PD-1 is highly expressed on chronically stimulated T cells, such as those specific for persistent viral or tumor antigens. PD-1 pathway blockade revolutionized cancer therapy in recent years. While response rates are higher than with chemotherapy, not all patients respond, and some develop autoimmune-like symptoms, or even overt autoimmunity. Herein, I sought to understand how the PD-1 pathway regulated islet-specific CD4+ T cells during type 1 diabetes (T1D) progression in non-obese diabetic (NOD) mice. Since insulin itself is one of the main antigens driving T1D, we developed insulin peptide:MHCII tetramer reagents to track insulin-reactive CD4+ T cells. Insulin-specific CD4+ T cells that expressed the most PD-1 also had the highest affinity for self, suggesting that PD-1 preferentially regulated those cells with the highest autoimmune potential. In NOD mice, the majority of insulin-specific CD4+ T cells had an anergic (tolerant) phenotype, but surprisingly, PD-1 blockade did not override the anergy program. These findings suggested that the differentiation state of the CD4+ T cell pre-determine its susceptibility to PD-1 blockade. Autoantibody production is a hallmark of autoimmunity, and has also been reported in patients treated with PD-1 blockade, suggesting that PD-1 might regulate this process. Autoantibody production results from B cell:CD4+ T cell interactions in the germinal center of the lymph node. The dynamics and regulation of the germinal center in spontaneous autoimmunity and after PD-1 blockade are not well understood, primarily due to an inability to track self-specific lymphocytes. To bridge this knowledge gap, we used tetramers to phenotype islet-specific CD4+ T cells and B cells in mice. PD-1- or PD-L1-deficient mice, as well as NOD mice treated with anti-PD-1, had increased insulin autoantibodies, as well as increased insulin-specific T follicular helper CD4+ T cells and germinal center B cells compared to controls. This increase was dependent on CD4+ T cell-intrinsic PD-1 signaling and relied on peptide:MHCII recognition. Taken together, my thesis work provides a mechanistic explanation for autoantibody onset following PD-1 blockade in the clinic, and has important implications for cancer immunotherapy and autoimmunity.","abstract_html":"Programmed death-1 (PD-1) is a T cell inhibitory receptor important for tolerance maintenance. PD-1 is highly expressed on chronically stimulated T cells, such as those specific for persistent viral or tumor antigens. PD-1 pathway blockade revolutionized cancer therapy in recent years. While response rates are higher than with chemotherapy, not all patients respond, and some develop autoimmune-like symptoms, or even overt autoimmunity. Herein, I sought to understand how the PD-1 pathway regulated islet-specific CD4+ T cells during type 1 diabetes (T1D) progression in non-obese diabetic (NOD) mice. Since insulin itself is one of the main antigens driving T1D, we developed insulin peptide:MHCII tetramer reagents to track insulin-reactive CD4+ T cells. Insulin-specific CD4+ T cells that expressed the most PD-1 also had the highest affinity for self, suggesting that PD-1 preferentially regulated those cells with the highest autoimmune potential. In NOD mice, the majority of insulin-specific CD4+ T cells had an anergic (tolerant) phenotype, but surprisingly, PD-1 blockade did not override the anergy program. These findings suggested that the differentiation state of the CD4+ T cell pre-determine its susceptibility to PD-1 blockade. Autoantibody production is a hallmark of autoimmunity, and has also been reported in patients treated with PD-1 blockade, suggesting that PD-1 might regulate this process. Autoantibody production results from B cell:CD4+ T cell interactions in the germinal center of the lymph node. The dynamics and regulation of the germinal center in spontaneous autoimmunity and after PD-1 blockade are not well understood, primarily due to an inability to track self-specific lymphocytes. To bridge this knowledge gap, we used tetramers to phenotype islet-specific CD4+ T cells and B cells in mice. PD-1- or PD-L1-deficient mice, as well as NOD mice treated with anti-PD-1, had increased insulin autoantibodies, as well as increased insulin-specific T follicular helper CD4+ T cells and germinal center B cells compared to controls. This increase was dependent on CD4+ T cell-intrinsic PD-1 signaling and relied on peptide:MHCII recognition. Taken together, my thesis work provides a mechanistic explanation for autoantibody onset following PD-1 blockade in the clinic, and has important implications for cancer immunotherapy and autoimmunity.","abstract_has_math":false,"creators":["Martinov, Tijana"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-12","date_published":"2018-12","updated_at":"2026-07-24T05:20:03Z","subjects":["autoantibody","autoimmunity","diabetes","insulin","programmed death-1","tetramer"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/11299/218699","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Martinov, Tijana"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2021-02-22T15:30:36Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2021-02-22T15:30:36Z"]},{"key":"dc:date.issued","label":"Date","values":["2018-12"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["autoantibody","autoimmunity","diabetes","insulin","programmed death-1","tetramer"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/11299/218699"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["University of Minnesota Ph.D. dissertation. 2018. Major: Microbiology, Immunology and Cancer Biology. Advisor: Brian Fife. 1 computer file (PDF); 159 pages."]},{"key":"dc:description.abstract","label":"Abstract","values":["Programmed death-1 (PD-1) is a T cell inhibitory receptor important for tolerance maintenance. PD-1 is highly expressed on chronically stimulated T cells, such as those specific for persistent viral or tumor antigens. PD-1 pathway blockade revolutionized cancer therapy in recent years. While response rates are higher than with chemotherapy, not all patients respond, and some develop autoimmune-like symptoms, or even overt autoimmunity. Herein, I sought to understand how the PD-1 pathway regulated islet-specific CD4+ T cells during type 1 diabetes (T1D) progression in non-obese diabetic (NOD) mice. Since insulin itself is one of the main antigens driving T1D, we developed insulin peptide:MHCII tetramer reagents to track insulin-reactive CD4+ T cells. Insulin-specific CD4+ T cells that expressed the most PD-1 also had the highest affinity for self, suggesting that PD-1 preferentially regulated those cells with the highest autoimmune potential. In NOD mice, the majority of insulin-specific CD4+ T cells had an anergic (tolerant) phenotype, but surprisingly, PD-1 blockade did not override the anergy program. These findings suggested that the differentiation state of the CD4+ T cell pre-determine its susceptibility to PD-1 blockade. Autoantibody production is a hallmark of autoimmunity, and has also been reported in patients treated with PD-1 blockade, suggesting that PD-1 might regulate this process. Autoantibody production results from B cell:CD4+ T cell interactions in the germinal center of the lymph node. The dynamics and regulation of the germinal center in spontaneous autoimmunity and after PD-1 blockade are not well understood, primarily due to an inability to track self-specific lymphocytes. To bridge this knowledge gap, we used tetramers to phenotype islet-specific CD4+ T cells and B cells in mice. PD-1- or PD-L1-deficient mice, as well as NOD mice treated with anti-PD-1, had increased insulin autoantibodies, as well as increased insulin-specific T follicular helper CD4+ T cells and germinal center B cells compared to controls. This increase was dependent on CD4+ T cell-intrinsic PD-1 signaling and relied on peptide:MHCII recognition. Taken together, my thesis work provides a mechanistic explanation for autoantibody onset following PD-1 blockade in the clinic, and has important implications for cancer immunotherapy and autoimmunity."]},{"key":"dc:title","label":"Title","values":["Programmed death-1 regulates islet-specific lymphocytes in type 1 diabetes"]}]}],"canonical_facts":{"dc:creator":["Martinov, Tijana"],"dc:date.accessioned":["2021-02-22T15:30:36Z"],"dc:date.available":["2021-02-22T15:30:36Z"],"dc:date.issued":["2018-12"],"dc:description":["University of Minnesota Ph.D. dissertation. 2018. Major: Microbiology, Immunology and Cancer Biology. Advisor: Brian Fife. 1 computer file (PDF); 159 pages."],"dc:description.abstract":["Programmed death-1 (PD-1) is a T cell inhibitory receptor important for tolerance maintenance. PD-1 is highly expressed on chronically stimulated T cells, such as those specific for persistent viral or tumor antigens. PD-1 pathway blockade revolutionized cancer therapy in recent years. While response rates are higher than with chemotherapy, not all patients respond, and some develop autoimmune-like symptoms, or even overt autoimmunity. Herein, I sought to understand how the PD-1 pathway regulated islet-specific CD4+ T cells during type 1 diabetes (T1D) progression in non-obese diabetic (NOD) mice. Since insulin itself is one of the main antigens driving T1D, we developed insulin peptide:MHCII tetramer reagents to track insulin-reactive CD4+ T cells. Insulin-specific CD4+ T cells that expressed the most PD-1 also had the highest affinity for self, suggesting that PD-1 preferentially regulated those cells with the highest autoimmune potential. In NOD mice, the majority of insulin-specific CD4+ T cells had an anergic (tolerant) phenotype, but surprisingly, PD-1 blockade did not override the anergy program. These findings suggested that the differentiation state of the CD4+ T cell pre-determine its susceptibility to PD-1 blockade. Autoantibody production is a hallmark of autoimmunity, and has also been reported in patients treated with PD-1 blockade, suggesting that PD-1 might regulate this process. Autoantibody production results from B cell:CD4+ T cell interactions in the germinal center of the lymph node. The dynamics and regulation of the germinal center in spontaneous autoimmunity and after PD-1 blockade are not well understood, primarily due to an inability to track self-specific lymphocytes. To bridge this knowledge gap, we used tetramers to phenotype islet-specific CD4+ T cells and B cells in mice. PD-1- or PD-L1-deficient mice, as well as NOD mice treated with anti-PD-1, had increased insulin autoantibodies, as well as increased insulin-specific T follicular helper CD4+ T cells and germinal center B cells compared to controls. This increase was dependent on CD4+ T cell-intrinsic PD-1 signaling and relied on peptide:MHCII recognition. Taken together, my thesis work provides a mechanistic explanation for autoantibody onset following PD-1 blockade in the clinic, and has important implications for cancer immunotherapy and autoimmunity."],"dc:identifier.uri":["https://hdl.handle.net/11299/218699"],"dc:language.iso":["en"],"dc:subject":["autoantibody","autoimmunity","diabetes","insulin","programmed death-1","tetramer"],"dc:title":["Programmed death-1 regulates islet-specific lymphocytes in type 1 diabetes"],"dc:type":["Thesis or Dissertation"]},"updated_at":"2026-07-24T05:20:03Z"}