Overcoming Nk-Mediated Rejection by Anti-3rd-Party Central Memory Veto CD8 T Cells Through Downregulation of Dnam-1 on Alloreactive Nk Cells

Authors

Wei-Hsin Liu
Aloukick Kumar Singh
Christa Blagdon
Sandeep Kumar Yadav
Einav Shoshan
Esther Bachar-Lustig
Yair Reisner

Publication Date

5-27-2025

Journal

Cell Reports

DOI

10.1016/j.celrep.2025.115674

PMID

40343795

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

Killer Cells, Natural, Animals, T Lineage-Specific Activation Antigen 1, CD8-Positive T-Lymphocytes, Mice, Antigens, Differentiation, T-Lymphocyte, Graft Rejection, Down-Regulation, Immunologic Memory, Hematopoietic Stem Cell Transplantation, Receptors, Virus, Mice, Inbred BALB C, Humans, Graft vs Host Disease, Transplantation, Homologous, CD155, CP: Immunology, Cbl protein, DNAM-1, Veto T cells, alloreactive NK cells

Published Open-Access

yes

Recommended Citation

Liu, Wei-Hsin; Singh, Aloukick Kumar; Blagdon, Christa; et al., "Overcoming Nk-Mediated Rejection by Anti-3rd-Party Central Memory Veto CD8 T Cells Through Downregulation of Dnam-1 on Alloreactive Nk Cells" (2025). Faculty, Staff and Student Publications. 4962.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4962