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

Oliver McCallion, Weijie Du, Viktor Glaser, Kate Milward, Sarah Short, Merve Bilici, Amy Cross, Helen Stark, Clemens Franke, Jonas Kath, Mikhail Valkov, Mingxing Yang, Leila Amini, Annette Künkele, Julia K. Polansky, Michael Schmueck-Henneresse, Hans-Dieter Volk, Petra Reinke, Dimitrios L. Wagner (), Joanna Hester () and Fadi Issa ()
Additional contact information
Oliver McCallion: University of Oxford
Weijie Du: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Viktor Glaser: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Kate Milward: University of Oxford
Sarah Short: University of Oxford
Merve Bilici: University of Oxford
Amy Cross: University of Oxford
Helen Stark: University of Oxford
Clemens Franke: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Jonas Kath: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Mikhail Valkov: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Mingxing Yang: Berlin Institute of Health at Charité – Universitätsmedizin Berlin
Leila Amini: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Annette Künkele: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Julia K. Polansky: Berlin Institute of Health at Charité – Universitätsmedizin Berlin
Michael Schmueck-Henneresse: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Hans-Dieter Volk: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Petra Reinke: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Dimitrios L. Wagner: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Joanna Hester: University of Oxford
Fadi Issa: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64945-3

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