HLA matching or CRISPR editing of HLA class I/II enables engraftment and effective function of allogeneic human regulatory T cell therapy in a humanized mouse transplantation model

McCallion, Oliver, Du, Weijie, Glaser, Viktor, Milward, Kate ORCID: https://orcid.org/0000-0003-3019-4443, Short, Sarah and Bilici, Merve 2025. HLA matching or CRISPR editing of HLA class I/II enables engraftment and effective function of allogeneic human regulatory T cell therapy in a humanized mouse transplantation model. Nature Communications 16 (1) , 9090. 10.1038/s41467-025-64945-3

PDF - Published Version Available under License Creative Commons Attribution. Download (4MB)

Abstract

Regulatory T cells (Tregs) hold promise for treating autoimmune disease and transplant rejection, yet generation of autologous products for adoptive transfer can suffer donor variability and slow turnaround, limiting their use in urgent indications. We therefore examine whether allogeneic, pre-manufactured (‘off-the-shelf’) Tregs could overcome these barriers. In a human skin-xenograft model, HLA-mismatched Tregs are swiftly eliminated by recipient CD8+ T cells and fail to protect grafts. Stringent matching of HLA class I and II restores efficacy but is clinically impractical. Using non-viral CRISPR editing we disrupt B2M and CIITA while inserting an HLA-E-B2M fusion, generating hypo-immunogenic Tregs that evade both T and NK cell attack. Engineered cells retain FOXP3 stability and potent in vitro suppression, and after a single low-dose infusion, prolong human skin graft survival in a humanized mouse model comparably to autologous Tregs. Histology and spatial transcriptomics reveal minimal cytotoxic infiltration and enrichment of immunoregulatory and tissue-repair programmes. Multiplex HLA engineering thus enables ready-to-use allogeneic Tregs that withstand host immune attack for adoptive transfer.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Additional Information:	Full list of authors available: http://dx.doi.org/10.1038/s41467-025-64945-3
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	10 July 2026
Date of Acceptance:	1 October 2025
Last Modified:	10 Jul 2026 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/188100

Actions (repository staff only)

Edit Item