Single-cell analysis of aplastic anemia reveals a convergence of NK and NK-like CD8+ T cells with a disease-associated TCR signature
- Author(s)
- Lundgren, S; Huuhtanen, J; Keränen, M; Feng, X; Patel, BA; Ryland, GL; Fox, LC; Bravo-Perez, C; Clemente, M; Kerr, C; Walldin, G; Dufva, O; Zaimoku, Y; Tuononen, T; Myllymäki, M; Ebeling, F; Jokinen, E; Heinonen, M; Kasanen, T; Klievink, J; Lähteenmäki, H; Jaatinen, T; Kytölä, S; Siitonen, S; Dulau-Florea, A; Braylan, R; Heinäniemi, M; Nakao, S; Hellström-Lindberg, E; Maciejewski, JP; Blombery, P; Young, NS; Lähdesmäki, H; Mustjoki, S;
- Details
- Publication Year 2025-02-26,Volume 17,Issue #787,Page eadl6758
- Journal Title
- Science Translational Medicine
- Publication Type
- Research article
- Abstract
- Immune aplastic anemia (AA) is a life-threatening bone marrow failure disorder driven by an autoimmune T cell attack against hematopoietic stem and progenitor cells (HSPCs). However, the exact autoantigen targets and role of other immune cells in the pathogenesis of AA are unknown. Here, we analyzed a cohort of 218 patients with AA using single-cell RNA and T cell receptor (TCR) αβ sequencing, TCRβ sequencing, flow cytometry, and plasma cytokine profiling. We identified natural killer (NK) cells and CD8(+) terminally differentiated effector T (T(EMRA)) cells expressing NK receptors with AA-associated TCRβ motifs as the most dysregulated immune cell populations in AA bone marrow. Functional coculture experiments using primary HSPCs and immune cells showed that NK cells cannot kill HSPCs alone but may sensitize HSPCs to CD8(+) T cell-mediated killing through production of interferons. Furthermore, HSPCs induced activation of T cell clones with CD8(+) T(EMRA) NK-like phenotype in coculture. Our results reveal a convergent phenotype of innate and adaptive immune cells that may drive AA.
- Keywords
- Humans; *Anemia, Aplastic/immunology/pathology; *Killer Cells, Natural/immunology/metabolism; *CD8-Positive T-Lymphocytes/immunology/metabolism; *Single-Cell Analysis; Adult; Female; Hematopoietic Stem Cells/metabolism; Male; Middle Aged; Cytokines/metabolism; Coculture Techniques; Receptors, Antigen, T-Cell/metabolism; Young Adult
- Department(s)
- Pathology; Haematology
- Publisher's Version
- https://doi.org/10.1126/scitranslmed.adl6758
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-03-21 02:49:48
Last Modified: 2025-03-21 02:54:49