Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients
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 receivi...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1601385/full |
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| author | Jaime Valentín-Quiroga Jaime Valentín-Quiroga Jaime Valentín-Quiroga Alejandro Zarauza-Santoveña Eduardo López-Collazo Leonardo M. R. Ferreira Leonardo M. R. Ferreira |
| author_facet | Jaime Valentín-Quiroga Jaime Valentín-Quiroga Jaime Valentín-Quiroga Alejandro Zarauza-Santoveña Eduardo López-Collazo Leonardo M. R. Ferreira Leonardo M. R. Ferreira |
| author_sort | Jaime Valentín-Quiroga |
| collection | DOAJ |
| description | 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 non-specifically target circulating antibodies and B cells, resulting in poor efficacy and complications. Regulatory T cells (Tregs) 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. |
| format | Article |
| id | doaj-art-dd182f2694de4d0a8a82ac1308c2c338 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-dd182f2694de4d0a8a82ac1308c2c3382025-08-20T03:05:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16013851601385Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipientsJaime Valentín-Quiroga0Jaime Valentín-Quiroga1Jaime Valentín-Quiroga2Alejandro Zarauza-Santoveña3Eduardo López-Collazo4Leonardo M. R. Ferreira5Leonardo M. R. Ferreira6Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesHollings Cancer Center, Medical University of South Carolina, Charleston, SC, United StatesThe Innate Immune Response Group, Hospital La Paz Institute for Health Research (IdiPAZ), University Hospital La Paz, Madrid, SpainPaediatric Nephrology Unit, University Hospital La Paz, Madrid, SpainThe Innate Immune Response Group, Hospital La Paz Institute for Health Research (IdiPAZ), University Hospital La Paz, Madrid, SpainDepartment of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesHollings Cancer Center, Medical University of South Carolina, Charleston, SC, United StatesOrgan 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 non-specifically target circulating antibodies and B cells, resulting in poor efficacy and complications. Regulatory T cells (Tregs) 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1601385/fullHLA sensitizationregulatory T cellsB cellsantibody productiontransplantationengineered immune receptors |
| spellingShingle | Jaime Valentín-Quiroga Jaime Valentín-Quiroga Jaime Valentín-Quiroga Alejandro Zarauza-Santoveña Eduardo López-Collazo Leonardo M. R. Ferreira Leonardo M. R. Ferreira Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients Frontiers in Immunology HLA sensitization regulatory T cells B cells antibody production transplantation engineered immune receptors |
| title | Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients |
| title_full | Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients |
| title_fullStr | Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients |
| title_full_unstemmed | Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients |
| title_short | Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients |
| title_sort | chimeric anti hla antibody receptor engineered human regulatory t cells suppress alloantigen specific b cells from pre sensitized transplant recipients |
| topic | HLA sensitization regulatory T cells B cells antibody production transplantation engineered immune receptors |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1601385/full |
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