Journal Article

DZNE-2025-00943

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A human NK cell progenitor that originates in the thymus and generates KIR+NKG2A- NK cells.

Reiß, J. ; Ghosh, S. ; Scheid, M. ; Graafen, L. ; Scherenschlich, N. ; Weinhold, S. ; Raba, K. ; Paulusch, S.DZNE* ; De Dominico, E.DZNE* ; Pham, T. X. U. ; Beyer, M.DZNE* ; Laws, H.-J. ; Niehues, T. ; Borkhardt, A. ; Uhrberg, M. ; Bennstein, S. B.

2025
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.adv9650

Abstract: KIR+NKG2A- natural killer (NK) cells have the unique ability to detect down-regulation of single HLA-I allotypes, frequently occurring in malignantly transformed and virus-infected cells. We have recently shown that circulating innate lymphoid cells 1 (cILC1s) have the potential to generate such KIR+NKG2A- NK cells, but their developmental origin was unknown. Here, we demonstrate that the development of cILC1 is thymus dependent and identify a putative progenitor of cILC1s in the thymus (thyILC1). Single-cell RNA sequencing analysis revealed a close relationship of thyILC1s to CD34+ double-negative thymocytes. Both generated comparable NK cell frequencies, while only thyILC1s could be efficiently differentiated into KIR+NKG2A- NK cells. Last, patients with FOXN1 haploinsufficiency, showing congenital thymic hypoplasia, exhibited a profound deficiency of cILC1s but not cILC2s and cILC3s, demonstrating their specific thymus dependency. Together, the data suggest that thyILC1s are the source of a thymus-dependent NK cell differentiation pathway that promotes generation of KIR+NKG2A- NK cells.

Keyword(s): Humans (MeSH) ; Killer Cells, Natural: metabolism (MeSH) ; Killer Cells, Natural: cytology (MeSH) ; Killer Cells, Natural: immunology (MeSH) ; Thymus Gland: cytology (MeSH) ; Thymus Gland: immunology (MeSH) ; Thymus Gland: metabolism (MeSH) ; NK Cell Lectin-Like Receptor Subfamily C: metabolism (MeSH) ; Cell Differentiation (MeSH) ; Receptors, KIR: metabolism (MeSH) ; NK Cell Lectin-Like Receptor Subfamily C ; Receptors, KIR ; KLRC1 protein, human

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Contributing Institute(s):

1. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
2. Platform for Single Cell Genomics and Epigenomics (PRECISE)
3. Immunogenomics and Neurodegeneration (AG Beyer)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)
3. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

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