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

Ben Hamza A, Welters C, Stadler S, Brüggemann M, Dietze K, Brauns O, Brümmendorf TH, Winkler T, Bullinger L, Blankenstein T, Rosenberger L, Leisegang M, Kammertöns T, Herr W, Moosmann A, Strobel J, Hackstein H, Dornmair K, Beier F, Hansmann L (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Blood American Society of Hematology

DOI: 10.1182/blood.2023023142

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.

Authors with CRIS profile

Thomas Winkler Professur für Genetik Julian Strobel Department of Transfusion Medicine and Haemostaseology Holger Hackstein Professur für Transfusionsmedizin und Cell-Engineering

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Miltenyi Biotec GmbH DE Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Klinikum der Universität München DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE)

How to cite

APA:

Ben Hamza, A., Welters, C., Stadler, S., Brüggemann, M., Dietze, K., Brauns, O.,... Hansmann, L. (2024). Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry. Blood. https://doi.org/10.1182/blood.2023023142

MLA:

Ben Hamza, Amin, et al. "Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry." Blood (2024).

BibTeX: Download