Ben Hamza, Amin and Welters, Carlotta and Stadler, Serena and Brueggemann, Monika and Dietze, Kerstin and Brauns, Olaf and Bruemmendorf, Tim H. and Winkler, Thomas and Bullinger, Lars and Blankenstein, Thomas and Rosenberger, Leonie and Leisegang, Matthias and Kammertoens, Thomas and Herr, Wolfgang and Moosmann, Andreas and Strobel, Julian and Hackstein, Holger and Dornmair, Klaus and Beier, Fabian and Hansmann, Leo (2024) Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry. BLOOD, 143 (14). pp. 1365-1378. ISSN 0006-4971, 1528-0020
Full text not available from this repository. (Request a copy)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 antithymocyte globulin strongly suggest critical roles for hematopoietic stem/progenitor cell-reactive T-cell clones in disease pathophysiology; however, their exact contribution and antigen speci fi cities 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 reexpressed 28 dominant T-cell receptors (TCRs) of 9 patients in reporter cell lines to determine reactivity with (1) in vitro-expanded CD34 + bone marrow, (2) CD34 - bone marrow, or (3) peptide pools covering immunodominant epitopes of highly prevalent viruses. Besides 5 cytomegalovirus-reactive TCRs, we identi fi ed 3 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 EpsteinBarr virus-derived latent membrane protein 1 (LMP1) presented on HLA-A*02:01. We identi fi ed 2 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EPSTEIN-BARR-VIRUS; BONE-MARROW; TARGET ANTIGENS; INFECTION; EXPANSION; RESPONSES; HUMANS |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Jan 2026 07:21 |
| Last Modified: | 22 Jan 2026 07:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65101 |
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