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| Item Type: | Article |
|---|---|
| Title: | Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry |
| Creators: |
Ben Hamza, A., Welters, C., Stadler, S., Brüggemann, M., Dietze, K., Brauns, O., Brümmendorf, T.H., Winkler, T.H., Bullinger, L.  ORCID: https://orcid.org/0000-0002-5890-5510, Blankenstein, T. ORCID: https://orcid.org/0000-0002-3357-4321, Rosenberger, L., Leisegang, M., Kammertöns, T., Herr, W., Moosmann, A., Strobel, J., Hackstein, H., Dornmair, K., Beier, F. and Hansmann, L.
|
| Abstract: | Acquired aplastic anemia is a bone marrow failure syndrome characterized by hypocellular bone marrow and peripheral blood pancytopenia. Frequent clinical responses to calcineurin inhibition and anti-thymocyte globulin strongly suggest critical roles for hematopoietic stem/progenitor cell-reactive T cell clones in disease pathophysiology; however, their exact contribution and antigen specificities remain unclear. We determined differentiation states and targets of dominant T cell clones along with their potential to eliminate hematopoietic progenitor cells in the bone marrow of 15 patients with acquired aplastic anemia. Single-cell sequencing and immunophenotyping revealed oligoclonal expansion and effector differentiation of CD8(+) T cell compartments. We re-expressed 28 dominant T cell receptors (TCRs) of nine patients in reporter cell lines to determine reactivity with i) in vitro expanded CD34(+) bone marrow, ii) CD34(-) bone marrow, or iii) peptide pools covering immunodominant epitopes of highly prevalent viruses. Besides five cytomegalovirus-reactive TCRs, we identified three TCRs that recognized antigen presented on hematopoietic progenitor cells. T cells transduced with these TCRs eliminated hematopoietic progenitor cells of the respective patients in vitro. One progenitor cell-reactive TCR (11A5) also recognized an epitope of the Epstein-Barr virus-derived latent membrane protein 1 (LMP1) presented on HLA A*02:01. We identified two LMP1-related mimotopes within the human proteome as activating targets of TCR 11A5 providing proof of concept that molecular mimicry of viral and self-epitopes can drive T cell-mediated elimination of hematopoietic progenitor cells in aplastic anemia. |
| Keywords: | Aplastic Anemia, Epstein-Barr Virus Infections, Hematopoietic Stem Cells, Human Herpesvirus 4, Molecular Mimicry, T-Cell Antigen Receptors |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 143 |
| Number: | 14 |
| Page Range: | 1365-1378 |
| Date: | 4 April 2024 |
| Additional Information: | Copyright © 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. |
| Official Publication: | https://doi.org/10.1182/blood.2023023142 |
| PubMed: | View item in PubMed |
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