Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry
Authors
- A. Ben Hamza
- C. Welters
- S. Stadler
- M. Brüggemann
- K. Dietze
- O. Brauns
- T.H. Brümmendorf
- T.H. Winkler
- L. Bullinger
- T. Blankenstein
- L. Rosenberger
- M. Leisegang
- T. Kammertöns
- W. Herr
- A. Moosmann
- J. Strobel
- H. Hackstein
- K. Dornmair
- F. Beier
- L. Hansmann
Journal
- Blood
Citation
- Blood 143 (14): 1365-1378
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.