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

Item Type:	Article
Title:	Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry
Creators Name:	Ben Hamza, A. and Welters, C. and Stadler, S. and Brüggemann, M. and Dietze, K. and Brauns, O. and Brümmendorf, T.H. and Winkler, T.H. and Bullinger, L. and Blankenstein, T. and Rosenberger, L. and Leisegang, M. and Kammertöns, T. and Herr, W. and Moosmann, A. and Strobel, J. and Hackstein, H. and Dornmair, K. and 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
Official Publication:	https://doi.org/10.1182/blood.2023023142
PubMed:	View item in PubMed

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