Single-cell analysis of aplastic anemia reveals a convergence of NK and NK-like CD8 <sup>+</sup> T cells with a disease-associated TCR signature
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<sup>+</sup> terminally differentiated effector T (T<sub>EMRA</sub>) 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<sup>+</sup> T cell-mediated killing through production of interferons. Furthermore, HSPCs induced activation of T cell clones with CD8<sup>+</sup> T<sub>EMRA</sub> NK-like phenotype in coculture. Our results reveal a convergent phenotype of innate and adaptive immune cells that may drive AA.
Authors
- Carlos Bravo‐Pérez (ORCID: https://orcid.org/0000-0001-9794-7847)
- Freja Ebeling (ORCID: https://orcid.org/0000-0002-7921-089X)
- Alina Dulau‐Florea (ORCID: https://orcid.org/0000-0003-3512-4946)
- Satu M. Mustjoki (ORCID: https://orcid.org/0000-0002-0816-8241)
- Sanna Siitonen
- Xingmin Feng (ORCID: https://orcid.org/0000-0001-8018-2366)
- Emmi Jokinen (ORCID: https://orcid.org/0000-0002-0060-6868)
- Shinji Nakao (ORCID: https://orcid.org/0000-0002-9674-624X)
- Olli Dufva (ORCID: https://orcid.org/0000-0002-8084-0282)
- Eva Hellström‐Lindberg (ORCID: https://orcid.org/0000-0002-7839-3743)
- Yoshitaka Zaimoku (ORCID: https://orcid.org/0000-0002-4108-5245)
- Michael J. Clemente (ORCID: https://orcid.org/0000-0003-4345-3934)
- Gunilla Walldin (ORCID: https://orcid.org/0009-0005-6663-6540)
- Harri J Lähdesmäki (ORCID: https://orcid.org/0000-0002-0373-139X)
- Piers A. Blombery (ORCID: https://orcid.org/0000-0002-9902-0022)
- Lucy C. Fox (ORCID: https://orcid.org/0000-0002-3855-8232)
- Jani Huuhtanen (ORCID: https://orcid.org/0000-0003-2750-4033)
- Mikko Keränen (ORCID: https://orcid.org/0000-0001-8027-499X)
- Georgina L. Ryland (ORCID: https://orcid.org/0000-0002-4990-0961)
- Raul C. Braylan
- Tiina Kasanen (ORCID: https://orcid.org/0000-0002-5408-1948)
- Sari Kytölä (ORCID: https://orcid.org/0000-0003-1649-8993)
- Hanna Lähteenmäki (ORCID: https://orcid.org/0000-0001-6773-2677)
- Neal S. Young (ORCID: https://orcid.org/0009-0007-0999-2519)
- Cassandra M Kerr (ORCID: https://orcid.org/0000-0002-2174-6560)
- Mikko Myllymäki (ORCID: https://orcid.org/0000-0002-8194-7356)
- Taina Jaatinen (ORCID: https://orcid.org/0000-0001-7783-6189)
- Jaroslaw Pawel Maciejewski (ORCID: https://orcid.org/0000-0002-6837-4346)
- Bhavisha A. Patel (ORCID: https://orcid.org/0000-0002-2974-7701)
- Jay Klievink (ORCID: https://orcid.org/0000-0002-4081-5840)
- Sofie Lundgren (ORCID: https://orcid.org/0000-0003-3146-9816)
- Markus Heinonen (ORCID: https://orcid.org/0000-0002-7741-2279)
- Tiina J Tuononen (ORCID: https://orcid.org/0009-0007-6677-3064)
Institutions
- Kanazawa University (JP)
- National Institutes of Health (US)
- Cleveland Clinic (US)
- Karolinska University Hospital (SE)
- University of Helsinki (FI)
- Kanazawa Medical University (JP)
- The University of Melbourne (AU)
- University of Eastern Finland (FI)
- Helsinki University Hospital (FI)
- Peter MacCallum Cancer Centre (AU)
- Finnish Red Cross (FI)
- Helsinki Institute for Information Technology (FI)
- Hospital General Universitario Morales Meseguer (ES)
- National Heart, Lung, and Blood Institute (US)
- Cancer Society of Finland (FI)
- National Institutes of Health Clinical Center (US)
- Hospital District of Helsinki and Uusimaa (FI)
- Aalto University (FI)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1126/scitranslmed.adl6758
- Citations
- 5
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.99