BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1601385
This article is part of the Research TopicRepurposing Cancer Immunotherapies for Use in Autoimmunity and TransplantationView all 8 articles
Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients
Provisionally accepted
- 1Medical University of South Carolina, Charleston, United States
- 2Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States
- 3University Hospital La Paz Research Institute (IdiPAZ), Madrid, Madrid, Spain
- 4University Hospital La Paz, La Paz, Madrid, Spain
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Organ transplantation is a lifesaving procedure, with 50,000 transplants happening every year in the United States. However, many patients harbor antibodies and B cells directed against allogeneic human leukocyte antigen (HLA) molecules, notably HLA-A2, greatly decreasing their likelihood of receiving a compatible organ. Moreover, antibody-mediated rejection is a significant contributor to chronic transplant rejection. Current strategies to desensitize patients nonspecifically target circulating antibodies and B cells, resulting in poor efficacy and complications.) are immune cells dedicated to suppressing specific immune responses by interacting with both innate and adaptive immune cells. Here, we genetically modified human Tregs with a chimeric anti-HLA antibody receptor (CHAR) consisting of an extracellular HLA-A2 protein fused to a CD28-CD3zeta intracellular signaling domain, driving Treg activation upon recognition of anti-HLA-A2 antibodies on the surface of alloreactive B cells. We find that HLA-A2 CHAR Tregs get activated specifically by anti-HLA-A2 antibody-producing cells. Of note, HLA-A2 CHAR activation does not negatively affect Treg stability, as measured by expression of the Treg lineage transcription factors FOXP3 and HELIOS. Interestingly, HLA-A2 CHAR Tregs are not cytotoxic towards anti-HLA-A2 antibody-producing cells, unlike HLA-A2 CHAR modified conventional CD4 + T cells. Importantly, HLA-A2 CHAR Tregs recognize and significantly suppress high affinity IgG antibody production by B cells from HLA-A2 sensitized patients. Altogether, our results provide proof-of-concept of a new strategy to specifically inhibit alloreactive B cells to desensitize transplant recipients.
Keywords: HLA sensitization, regulatory T cells, B cells, antibody production, Transplantation, engineered immune receptors, human immunology
Received: 27 Mar 2025; Accepted: 23 Jul 2025.
Copyright: © 2025 Valentín, Zarauza-Santoveña, López-Collazo and Ferreira. 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: Leonardo M.R. Ferreira, Medical University of South Carolina, Charleston, United States
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