Exploring Veto Activity: DNAM-1-CD155 Axis in Overcoming NK Cell-Mediated Allo-Rejection and Applications for CAR-T Cell Therapy

<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>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Liu, Wei-Hsin
• <p>https://orcid.org/0000-0003-4670-7485</p>

Contributors dc:contributor

• Yair Reisner
• Gheath Al-Atrash
• Jeffrey Joel Molldrem

• 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

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1426

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2483