Details

Autor(en) / Beteiligte

• Ben Hamza, Amin
• Welters, Carlotta
• Stadler, Serena
• Brüggemann, Monika
• Dietze, Kerstin
• Brauns, Olaf
• Brümmendorf, Tim H.
• Winkler, Thomas
• Bullinger, Lars
• Blankenstein, Thomas
• Rosenberger, Leonie
• Leisegang, Matthias
• Kammertöns, Thomas
• Herr, Wolfgang
• Moosmann, Andreas
• Strobel, Julian
• Hackstein, Holger
• Dornmair, Klaus
• Beier, Fabian
• Hansmann, Leo

Titel

Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry

Ist Teil von

• Blood, 2024-04, Vol.143 (14), p.1365-1378

Erscheinungsjahr

2024

Beschreibungen/Notizen

• 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 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 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 identified 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 Epstein-Barr virus–derived latent membrane protein 1 (LMP1) presented on HLA-A∗02:01. We identified 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.