INVESTIGATING THE DISTINCT ROLE OF PD-L2 IN MODULATING HUMAN T CELL RESPONSES
Anupallavi Srinivasamani, M.S.
Advisory Professor: Michael A. Curran, Ph.D.
Therapeutic blockade of the Programmed cell death-1 (PD-1) receptor and its ligand Programmed death ligand-1 (PD-L1) has revolutionized the treatment of multiple cancers and made durable tumor regression a possibility in the clinic. PD-1 blockade prolonged progression-free survival and overall survival with lesser high-grade toxicity in patients with advanced melanoma when compared to the other FDA-approved checkpoint blockade target, CTLA-4. Unlike CTLA-4, PD-1 is unique in its ability to regulate T cell functions in lymphoid tissues as well as in non-lymphoid tissues like the tumor microenvironment. The comparatively lower incidence of immune-related adverse events associated with PD-1 blockade and its wide-ranging immune-modulatory functions makes PD-1 signaling axis especially favorable for next-generation of combination therapies aimed at increasing the clinical efficacy of immune checkpoint blockade beyond the current 20% of patients who are expected to positively respond to PD-1/PD-L1 blockade. The current and future development of novel therapeutics targeting the PD-1 signaling axis should be rationally guided by a comprehensive understanding of the immunobiology underlying PD-1 signaling. However, the highest affinity ligand of PD-1, PD-L2 remains understudied and has yet to be directly interrogated for therapeutic potential. Recent reports have begun to reveal the relevance of PD-L2 in tumor immunology, however, critical gaps in our knowledge about the function of PD-L2, particularly in humans, limit efforts to rationally harness its potential clinical benefit. We therefore investigated the distinct function of PD-L2 in the PD-1/PD-L1/PD-L2 signaling axis in human T cells. To this end, we established an in vitro experimental system using human Jurkat T cells that allowed us to study the T cell regulatory functions of PD-1/PD-L1 and PD-1/PD-L2 complexes, exclusive of other protein-protein interactions on the surface of T cells. We resolved the contention over the nature of T cell regulation mediated by PD-L2 in preclinical murine models and conclusively showed that PD-L2 is solely a co-inhibitory ligand of human T cells. We also discovered the capacity of PD-L1 and PD-L2 to heterodimerize and studied the functional consequence of this interaction on T cell signaling. Despite binding to the same receptor, we demonstrated that PD-L1 and PD-L2 differentially engage PD-1 to induce a distinct inhibitory signaling cascade downstream of PD-1 in human T cells. We characterized the differences in the molecular mechanisms of PD-1/PD-L1 and PD-1/PD-L2 mediated inhibition of primary human T cells and elucidated the physiological impact of the differential signaling induced by PD-ligands through PD-1 on T cell function. Taken together, our work provides a more solid immunobiological foundation for clinical translation of PD-L2 and defines its non-redundant role in regulating T cell immunity in humans.
","abstract_html":"<p><strong>INVESTIGATING THE DISTINCT ROLE OF PD-L2 IN MODULATING HUMAN T CELL RESPONSES</strong></p> <p>Anupallavi Srinivasamani, M.S.</p> <p>Advisory Professor: Michael A. Curran, Ph.D.</p> <p>Therapeutic blockade of the Programmed cell death-1 (PD-1) receptor and its ligand Programmed death ligand-1 (PD-L1) has revolutionized the treatment of multiple cancers and made durable tumor regression a possibility in the clinic. PD-1 blockade prolonged progression-free survival and overall survival with lesser high-grade toxicity in patients with advanced melanoma when compared to the other FDA-approved checkpoint blockade target, CTLA-4. Unlike CTLA-4, PD-1 is unique in its ability to regulate T cell functions in lymphoid tissues as well as in non-lymphoid tissues like the tumor microenvironment. The comparatively lower incidence of immune-related adverse events associated with PD-1 blockade and its wide-ranging immune-modulatory functions makes PD-1 signaling axis especially favorable for next-generation of combination therapies aimed at increasing the clinical efficacy of immune checkpoint blockade beyond the current 20% of patients who are expected to positively respond to PD-1/PD-L1 blockade. The current and future development of novel therapeutics targeting the PD-1 signaling axis should be rationally guided by a comprehensive understanding of the immunobiology underlying PD-1 signaling. However, the highest affinity ligand of PD-1, PD-L2 remains understudied and has yet to be directly interrogated for therapeutic potential. Recent reports have begun to reveal the relevance of PD-L2 in tumor immunology, however, critical gaps in our knowledge about the function of PD-L2, particularly in humans, limit efforts to rationally harness its potential clinical benefit. We therefore investigated the distinct function of PD-L2 in the PD-1/PD-L1/PD-L2 signaling axis in human T cells. To this end, we established an in vitro experimental system using human Jurkat T cells that allowed us to study the T cell regulatory functions of PD-1/PD-L1 and PD-1/PD-L2 complexes, exclusive of other protein-protein interactions on the surface of T cells. We resolved the contention over the nature of T cell regulation mediated by PD-L2 in preclinical murine models and conclusively showed that PD-L2 is solely a co-inhibitory ligand of human T cells. We also discovered the capacity of PD-L1 and PD-L2 to heterodimerize and studied the functional consequence of this interaction on T cell signaling. Despite binding to the same receptor, we demonstrated that PD-L1 and PD-L2 differentially engage PD-1 to induce a distinct inhibitory signaling cascade downstream of PD-1 in human T cells. We characterized the differences in the molecular mechanisms of PD-1/PD-L1 and PD-1/PD-L2 mediated inhibition of primary human T cells and elucidated the physiological impact of the differential signaling induced by PD-ligands through PD-1 on T cell function. Taken together, our work provides a more solid immunobiological foundation for clinical translation of PD-L2 and defines its non-redundant role in regulating T cell immunity in humans.</p>","abstract_has_math":false,"creators":["Srinivasamani, Anupallavi",""],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Dr. Michael Curran","Dr. Stephanie Watowich","Dr. Pamela Wenzel"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-08-01T07:00:00Z","date_published":"2023-08-01T07:00:00Z","updated_at":"2026-07-24T05:50:02Z","subjects":["Immune checkpoint inhibitors","PD-L2","T cell signaling","PD-L1","Immunotherapy","Immunity","Immunology and Infectious Disease","Life Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1285","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Dr. Michael Curran","Dr. Stephanie Watowich","Dr. Pamela Wenzel"]},{"key":"dc:creator","label":"Author","values":["Srinivasamani, Anupallavi",""]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2024-06-05T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Immune checkpoint inhibitors","PD-L2","T cell signaling","PD-L1","Immunotherapy","Immunity","Immunology and Infectious Disease","Life Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1285"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["INVESTIGATING THE DISTINCT ROLE OF PD-L2 IN MODULATING HUMAN T CELL RESPONSES
Anupallavi Srinivasamani, M.S.
Advisory Professor: Michael A. Curran, Ph.D.
Therapeutic blockade of the Programmed cell death-1 (PD-1) receptor and its ligand Programmed death ligand-1 (PD-L1) has revolutionized the treatment of multiple cancers and made durable tumor regression a possibility in the clinic. PD-1 blockade prolonged progression-free survival and overall survival with lesser high-grade toxicity in patients with advanced melanoma when compared to the other FDA-approved checkpoint blockade target, CTLA-4. Unlike CTLA-4, PD-1 is unique in its ability to regulate T cell functions in lymphoid tissues as well as in non-lymphoid tissues like the tumor microenvironment. The comparatively lower incidence of immune-related adverse events associated with PD-1 blockade and its wide-ranging immune-modulatory functions makes PD-1 signaling axis especially favorable for next-generation of combination therapies aimed at increasing the clinical efficacy of immune checkpoint blockade beyond the current 20% of patients who are expected to positively respond to PD-1/PD-L1 blockade. The current and future development of novel therapeutics targeting the PD-1 signaling axis should be rationally guided by a comprehensive understanding of the immunobiology underlying PD-1 signaling. However, the highest affinity ligand of PD-1, PD-L2 remains understudied and has yet to be directly interrogated for therapeutic potential. Recent reports have begun to reveal the relevance of PD-L2 in tumor immunology, however, critical gaps in our knowledge about the function of PD-L2, particularly in humans, limit efforts to rationally harness its potential clinical benefit. We therefore investigated the distinct function of PD-L2 in the PD-1/PD-L1/PD-L2 signaling axis in human T cells. To this end, we established an in vitro experimental system using human Jurkat T cells that allowed us to study the T cell regulatory functions of PD-1/PD-L1 and PD-1/PD-L2 complexes, exclusive of other protein-protein interactions on the surface of T cells. We resolved the contention over the nature of T cell regulation mediated by PD-L2 in preclinical murine models and conclusively showed that PD-L2 is solely a co-inhibitory ligand of human T cells. We also discovered the capacity of PD-L1 and PD-L2 to heterodimerize and studied the functional consequence of this interaction on T cell signaling. Despite binding to the same receptor, we demonstrated that PD-L1 and PD-L2 differentially engage PD-1 to induce a distinct inhibitory signaling cascade downstream of PD-1 in human T cells. We characterized the differences in the molecular mechanisms of PD-1/PD-L1 and PD-1/PD-L2 mediated inhibition of primary human T cells and elucidated the physiological impact of the differential signaling induced by PD-ligands through PD-1 on T cell function. Taken together, our work provides a more solid immunobiological foundation for clinical translation of PD-L2 and defines its non-redundant role in regulating T cell immunity in humans.
"]},{"key":"dc:title","label":"Title","values":["Investigating The Distinct Role of Pd-L2 In Modulating Human T Cells Responses"]}]}],"canonical_facts":{"dc:contributor":["Dr. Michael Curran","Dr. Stephanie Watowich","Dr. Pamela Wenzel"],"dc:creator":["Srinivasamani, Anupallavi",""],"dc:date.available":["2024-06-05T07:00:00Z"],"dc:description.abstract":["INVESTIGATING THE DISTINCT ROLE OF PD-L2 IN MODULATING HUMAN T CELL RESPONSES
Anupallavi Srinivasamani, M.S.
Advisory Professor: Michael A. Curran, Ph.D.
Therapeutic blockade of the Programmed cell death-1 (PD-1) receptor and its ligand Programmed death ligand-1 (PD-L1) has revolutionized the treatment of multiple cancers and made durable tumor regression a possibility in the clinic. PD-1 blockade prolonged progression-free survival and overall survival with lesser high-grade toxicity in patients with advanced melanoma when compared to the other FDA-approved checkpoint blockade target, CTLA-4. Unlike CTLA-4, PD-1 is unique in its ability to regulate T cell functions in lymphoid tissues as well as in non-lymphoid tissues like the tumor microenvironment. The comparatively lower incidence of immune-related adverse events associated with PD-1 blockade and its wide-ranging immune-modulatory functions makes PD-1 signaling axis especially favorable for next-generation of combination therapies aimed at increasing the clinical efficacy of immune checkpoint blockade beyond the current 20% of patients who are expected to positively respond to PD-1/PD-L1 blockade. The current and future development of novel therapeutics targeting the PD-1 signaling axis should be rationally guided by a comprehensive understanding of the immunobiology underlying PD-1 signaling. However, the highest affinity ligand of PD-1, PD-L2 remains understudied and has yet to be directly interrogated for therapeutic potential. Recent reports have begun to reveal the relevance of PD-L2 in tumor immunology, however, critical gaps in our knowledge about the function of PD-L2, particularly in humans, limit efforts to rationally harness its potential clinical benefit. We therefore investigated the distinct function of PD-L2 in the PD-1/PD-L1/PD-L2 signaling axis in human T cells. To this end, we established an in vitro experimental system using human Jurkat T cells that allowed us to study the T cell regulatory functions of PD-1/PD-L1 and PD-1/PD-L2 complexes, exclusive of other protein-protein interactions on the surface of T cells. We resolved the contention over the nature of T cell regulation mediated by PD-L2 in preclinical murine models and conclusively showed that PD-L2 is solely a co-inhibitory ligand of human T cells. We also discovered the capacity of PD-L1 and PD-L2 to heterodimerize and studied the functional consequence of this interaction on T cell signaling. Despite binding to the same receptor, we demonstrated that PD-L1 and PD-L2 differentially engage PD-1 to induce a distinct inhibitory signaling cascade downstream of PD-1 in human T cells. We characterized the differences in the molecular mechanisms of PD-1/PD-L1 and PD-1/PD-L2 mediated inhibition of primary human T cells and elucidated the physiological impact of the differential signaling induced by PD-ligands through PD-1 on T cell function. Taken together, our work provides a more solid immunobiological foundation for clinical translation of PD-L2 and defines its non-redundant role in regulating T cell immunity in humans.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1285"],"dc:subject":["Immune checkpoint inhibitors","PD-L2","T cell signaling","PD-L1","Immunotherapy","Immunity","Immunology and Infectious Disease","Life Sciences"],"dc:title":["Investigating The Distinct Role of Pd-L2 In Modulating Human T Cells Responses"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:02Z"}