As Miller et al. defined veto activity, it enables cells to target host cytotoxic T lymphocyte (CTL) precursors specific to veto cells' antigens, selectively eliminating anti- donor T cell clones without inducing rejection. By leveraging this unique immune property, two key research aims were proposed: “Exploration of the Impact of Veto Activity on Natural Killer (NK) Cell-Mediated Allo-rejection” and “Development of Off-the- shelf Chimeric Antigen Receptor (CAR)-T Therapy: Engineering Anti-Viral Veto CD8+ T Cells”. As demonstrated in our previous research, in a murine model with mild conditioning, anti-third-party central memory CD8+ veto T cells (veto Tcm) can prevent T cell- mediated graft rejection without causing significant graft-versus-host disease (GvHD). These veto Tcm eliminate donor-specific T cell clones via a Fas-FasL-signaling pathway. However, the underlying mechanism of their interaction with alloreactive NK cells remains elusive. By transplanting nude mice with allogeneic T cell-depleted bone marrow cells (TDBM), we demonstrated that veto Tcm cells effectively overcome NK cell-mediated rejection. We also discovered that veto Tcm cells upregulate CD155, a primary ligand for the activating receptor DNAM-1. Later in vitro studies further indicated that conjugation between veto Tcm cells and alloreactive NK cells induces NK cell anergy by enhancing the internalization and degradation of DNAM-1, a process significantly linked to the activation of the Cbl protein in alloreactive NK cells. Next, we aim to develop off-the-shelf CAR-T cells to translate this approach into human clinical applications using this novel platform. By triggering veto activity of cytotoxic CD8 T cells and selectively expanding clones specific to viral peptides, we can effectively address the challenges of graft rejection and GvHD. CD19 Veto CAR-T cells, generated via retroviral transduction, demonstrated promising anti-tumor effects in vitro and in vivo without inducing GvHD. These findings highlight that veto Tcm can serve as a promising platform for CAR-T cell therapy, potentially avoiding the need for extensive gene editing to mitigate the risks of bi-directional alloreactivity.
","abstract_html":"<p>As Miller et al. defined veto activity, it enables cells to target host cytotoxic T lymphocyte (CTL) precursors specific to veto cells' antigens, selectively eliminating anti- donor T cell clones without inducing rejection. By leveraging this unique immune property, two key research aims were proposed: “Exploration of the Impact of Veto Activity on Natural Killer (NK) Cell-Mediated Allo-rejection” and “Development of Off-the- shelf Chimeric Antigen Receptor (CAR)-T Therapy: Engineering Anti-Viral Veto CD8+ T Cells”. As demonstrated in our previous research, in a murine model with mild conditioning, anti-third-party central memory CD8+ veto T cells (veto Tcm) can prevent T cell- mediated graft rejection without causing significant graft-versus-host disease (GvHD). These veto Tcm eliminate donor-specific T cell clones via a Fas-FasL-signaling pathway. However, the underlying mechanism of their interaction with alloreactive NK cells remains elusive. By transplanting nude mice with allogeneic T cell-depleted bone marrow cells (TDBM), we demonstrated that veto Tcm cells effectively overcome NK cell-mediated rejection. We also discovered that veto Tcm cells upregulate CD155, a primary ligand for the activating receptor DNAM-1. Later in vitro studies further indicated that conjugation between veto Tcm cells and alloreactive NK cells induces NK cell anergy by enhancing the internalization and degradation of DNAM-1, a process significantly linked to the activation of the Cbl protein in alloreactive NK cells. Next, we aim to develop off-the-shelf CAR-T cells to translate this approach into human clinical applications using this novel platform. By triggering veto activity of cytotoxic CD8 T cells and selectively expanding clones specific to viral peptides, we can effectively address the challenges of graft rejection and GvHD. CD19 Veto CAR-T cells, generated via retroviral transduction, demonstrated promising anti-tumor effects in vitro and in vivo without inducing GvHD. These findings highlight that veto Tcm can serve as a promising platform for CAR-T cell therapy, potentially avoiding the need for extensive gene editing to mitigate the risks of bi-directional alloreactivity.</p>","abstract_has_math":false,"creators":["Liu, Wei-Hsin","https://orcid.org/0000-0003-4670-7485
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Yair Reisner","Gheath Al-Atrash","Jeffrey Joel Molldrem"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-05-01T07:00:00Z","date_published":"2025-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:08Z","subjects":["Veto T Cell","Alloreactive Natural Killer Cell","Allo-rejection","CD155","DNAM-1","Off-the-Shelf CAR-T Cell Therapy","Immunity","Immunotherapy","Molecular, Cellular, and Tissue Engineering"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1426","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Yair Reisner","Gheath Al-Atrash","Jeffrey Joel Molldrem"]},{"key":"dc:creator","label":"Author","values":["Liu, Wei-Hsin","https://orcid.org/0000-0003-4670-7485
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"]},{"key":"dc:title","label":"Title","values":["Exploring Veto Activity: DNAM-1-CD155 Axis in Overcoming NK Cell-Mediated Allo-Rejection and Applications for CAR-T Cell Therapy"]}]}],"canonical_facts":{"dc:contributor":["Yair Reisner","Gheath Al-Atrash","Jeffrey Joel Molldrem"],"dc:creator":["Liu, Wei-Hsin","https://orcid.org/0000-0003-4670-7485
"],"dc:date.available":["2026-04-22T07:00:00Z"],"dc:description.abstract":["As Miller et al. defined veto activity, it enables cells to target host cytotoxic T lymphocyte (CTL) precursors specific to veto cells' antigens, selectively eliminating anti- donor T cell clones without inducing rejection. By leveraging this unique immune property, two key research aims were proposed: “Exploration of the Impact of Veto Activity on Natural Killer (NK) Cell-Mediated Allo-rejection” and “Development of Off-the- shelf Chimeric Antigen Receptor (CAR)-T Therapy: Engineering Anti-Viral Veto CD8+ T Cells”. As demonstrated in our previous research, in a murine model with mild conditioning, anti-third-party central memory CD8+ veto T cells (veto Tcm) can prevent T cell- mediated graft rejection without causing significant graft-versus-host disease (GvHD). These veto Tcm eliminate donor-specific T cell clones via a Fas-FasL-signaling pathway. However, the underlying mechanism of their interaction with alloreactive NK cells remains elusive. By transplanting nude mice with allogeneic T cell-depleted bone marrow cells (TDBM), we demonstrated that veto Tcm cells effectively overcome NK cell-mediated rejection. We also discovered that veto Tcm cells upregulate CD155, a primary ligand for the activating receptor DNAM-1. Later in vitro studies further indicated that conjugation between veto Tcm cells and alloreactive NK cells induces NK cell anergy by enhancing the internalization and degradation of DNAM-1, a process significantly linked to the activation of the Cbl protein in alloreactive NK cells. Next, we aim to develop off-the-shelf CAR-T cells to translate this approach into human clinical applications using this novel platform. By triggering veto activity of cytotoxic CD8 T cells and selectively expanding clones specific to viral peptides, we can effectively address the challenges of graft rejection and GvHD. CD19 Veto CAR-T cells, generated via retroviral transduction, demonstrated promising anti-tumor effects in vitro and in vivo without inducing GvHD. These findings highlight that veto Tcm can serve as a promising platform for CAR-T cell therapy, potentially avoiding the need for extensive gene editing to mitigate the risks of bi-directional alloreactivity.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1426"],"dc:subject":["Veto T Cell","Alloreactive Natural Killer Cell","Allo-rejection","CD155","DNAM-1","Off-the-Shelf CAR-T Cell Therapy","Immunity","Immunotherapy","Molecular, Cellular, and Tissue Engineering"],"dc:title":["Exploring Veto Activity: DNAM-1-CD155 Axis in Overcoming NK Cell-Mediated Allo-Rejection and Applications for CAR-T Cell Therapy"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:08Z"}