Reiß Julian, Ghosh Sujal, Scheid Michael, Graafen Lea, Scherenschlich Nadine, Weinhold Sandra, Raba Katharina, Paulusch Stefan, De Dominico Elena, Pham Thi X U, Beyer Marc, Laws Hans-Jürgen, Niehues Tim, Borkhardt Arndt, Uhrberg Markus, Bennstein Sabrina B
Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, Düsseldorf, Germany.
Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
Sci Adv. 2025 Aug 8;11(32):eadv9650. doi: 10.1126/sciadv.adv9650.
KIRNKG2A 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 KIRNKG2A 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 KIRNKG2A NK cells. Last, patients with 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 KIRNKG2A NK cells.
杀伤细胞免疫球蛋白样受体KIR2DL2和KIR2DL3（KIRNKG2A）自然杀伤（NK）细胞具有独特能力，可检测单一人类白细胞抗原I类（HLA-I）同种异型的下调，这种情况常见于恶性转化细胞和病毒感染细胞。我们最近发现，循环性固有淋巴细胞1（cILC1）有潜力产生此类KIRNKG2A NK细胞，但其发育起源尚不清楚。在此，我们证明cILC1的发育依赖胸腺，并确定了胸腺中cILC1的假定祖细胞（胸腺ILC1，thyILC1）。单细胞RNA测序分析显示，thyILC1与CD34双阴性胸腺细胞密切相关。二者产生的NK细胞频率相当，但只有thyILC1能够有效分化为KIRNKG2A NK细胞。最后，患有单倍体不足、表现为先天性胸腺发育不全的患者，其cILC1严重缺乏，但cILC2和cILC3未受影响，表明它们对胸腺有特异性依赖。总之，这些数据表明，thyILC1是胸腺依赖性NK细胞分化途径的来源，该途径促进KIRNKG2A NK细胞的产生。
