Overcoming NK-mediated rejection by anti-3rd-party central memory veto CD8 T cells through downregulation of DNAM-1 on alloreactive NK cells

  • Cell Rep. 2025 May 27;44(5):115674. doi: 10.1016/j.celrep.2025.115674.
Wei-Hsin Liu  1 ,  Aloukick Kumar Singh  2 ,  Christa Blagdon  3 ,  Sandeep Kumar Yadav  4 ,  Einav Shoshan  3 ,  Esther Bachar-Lustig  3 ,  Yair Reisner  5
Affiliations
  • 1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 2. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Immunology and Regenerative Biology Department, Weizmann Institute of Science, Rehovot, Israel. Electronic address: [email protected].
PMID: 40343795 DOI: 10.1016/j.celrep.2025.115674
Abstract

Anti-3rd-party central memory veto CD8 T (veto Tcm) cells can overcome T cell-mediated graft rejection under mild conditioning without causing significant graft versus host disease (GVHD). We previously demonstrated that these veto Tcm cells can effectively delete anti-donor T cell clones through a Fas-FasL mechanism, whereas their ability to neutralize alloreactive natural killer (NK) cells and the mechanism of such potential activity remained unknown. Using "nude" mice as recipients of allogeneic T cell-depleted hematopoietic stem cell transplantation (HSCT), we demonstrate effective inhibition of NK-mediated rejection by Tcm cells. Ex vivo studies revealed that Tcm cells express high levels of CD155, the ligand of the activating receptor DNAX accessory molecule-1 (DNAM-1). Conjugate formation between alloreactive NK cells and the veto cells induces NK anergy through a unique mechanism mediated by DNAM-1 internalization and degradation. These insights on veto Tcm cells and their impact on alloreactive NK cells offer potential translational approaches for haploidentical bone marrow transplantation and off-the-shelf chimeric antigen receptor (CAR) cell therapies.

Keywords
CD155; CP: Immunology; Cbl protein; DNAM-1; Veto T cells; alloreactive NK cells.
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