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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1513009
This article is part of the Research Topic Repurposing Cancer Immunotherapies for Use in Autoimmunity and Transplantation View all 7 articles
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Secondary and tertiary lymphoid structures are a critical target of suppression in many autoimmune disorders, protein replacement therapies, and in transplantation. Although antigen-specific regulatory T cells (Tregs), such as chimeric antigen receptor (CAR) Tregs, generally persist longer and localize to target tissues more effectively than polyclonal Tregs in animal models, their numbers still progressively decline over time. A potential approach to maximize Treg activity in vivo is the expression of chemokine receptors such as CXCR5, which would enable localization of a greater number of engineered cells at sites of antigen presentation. Indeed, CXCR5 expression on follicular T helper cells and follicular Tregs enables migration toward lymph nodes, B cell zones, and tertiary lymphoid structures that appear in chronically inflamed non-lymphoid tissues. In this study, we generated human and murine CXCR5 co-expressing engineered receptor Tregs and tested them in preclinical mouse models of allo-immunity and hemophilia A, respectively. In vitro, anti-HLA-A2 CXCR5 + CAR-Tregs showed enhanced migratory and antigen-specific suppressive capacities compared to untransduced Tregs. When injected into an NSG mouse model of HLA-A2 + pancreatic islet transplantation, anti-HLA-A2 CXCR5 + CAR-Tregs maintained a good safety profile allowing for long-term graft survival in contrast to anti-HLA-A2 CXCR5 + conventional CAR-T (Tconv) cells that eliminated the graft. Additionally, we engineered a murine CXCR5 co-expressing clotting factor VIII (FVIII) specific T cell receptor fusion construct epsilon (FVIII TRuCe CXCR5 Treg), which improved in vivo Treg persistence and suppressive capacity in a model of FVIII replacement therapy for hemophilia A. Collectively, our findings indicate that CXCR5 co-expression is safe and enhances in vivo localization and persistence in target tissues. This strategy can potentially promote targeted tolerance without the risk of off-target effects in multiple disease models.
Keywords: Regulatory T cells (Tregs), C-X-C chemokine receptor type 5 (CXCR5), Type 1 diabetes (T1D), Pancreatic islet transplantation, Hemophilia, chimeric antigen receptor (CAR), TCR fusion construct epsilon (TRuCe)
Received: 17 Oct 2024; Accepted: 25 Mar 2025.
Copyright: © 2025 Doglio, Rana, Stucchi, Melero, Ugolini, Jofra, Kumar, Monti, Martini, Thirumurugan, Biswas, Bonini and Fousteri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Moanaro Biswas, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
Chiara Bonini, Experimental Hematology Unit, Division of Immunology,Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, 20132, Lombardy, Italy
Georgia Fousteri, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute (IRCCS), Milan, 20132, Lombardy, Italy
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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