Details

Autor(en) / Beteiligte

• Sohlberg, Ebba
• Pfefferle, Aline
• Heggernes Ask, Eivind
• Tschan-Plessl, Astrid
• Jacobs, Benedikt
• Netskar, Herman
• Lorenz, Susanne
• Kanaya, Minoru
• Kosugi-Kanaya, Mizuha
• Meinke, Stephan
• Mörtberg, Anette
• Höglund, Petter
• Sundin, Mikael
• Carlsson, Göran
• Palmblad, Jan
• Malmberg, Karl-Johan

Titel

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Ist Teil von

• Blood, 2022-02, Vol.139 (5), p.704-716

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Neutrophils have been thought to play a critical role in terminal differentiation of NK cells. Whether this effect is direct or a consequence of global immune changes with effects on NK-cell homeostasis remains unknown. In this study, we used high-resolution flow and mass cytometry to examine NK-cell repertoires in 64 patients with neutropenia and 27 healthy age- and sex-matched donors. A subgroup of patients with chronic neutropenia showed severely disrupted NK-cell homeostasis manifesting as increased frequencies of CD56bright NK cells and a lack of mature CD56dim NK cells. These immature NK-cell repertoires were characterized by expression of the proliferation/exhaustion markers Ki-67, Tim-3, and TIGIT and displayed blunted tumor target cell responses. Systems-level immune mapping revealed that the changes in immunophenotypes were confined to NK cells, leaving T-cell differentiation intact. RNA sequencing of NK cells from these patients showed upregulation of a network of genes, including TNFSF9, CENPF, MKI67, and TOP2A, associated with apoptosis and the cell cycle, but different from the conventional CD56bright signatures. Profiling of 249 plasma proteins showed a coordinated enrichment of pathways related to apoptosis and cell turnover, which correlated with immature NK-cell repertoires. Notably, most of these patients exhibited severe-grade neutropenia, suggesting that the profoundly altered NK-cell homeostasis was connected to the severity of their underlying etiology. Hence, although our data suggest that neutrophils are dispensable for NK-cell development and differentiation, some patients displayed a specific gap in the NK repertoire, associated with poor cytotoxic function and more severe disease manifestations. •Systems-level immune profiling reveals perturbed NK-cell homeostasis in a subgroup of patients with chronic severe-grade neutropenia.•Coordinated transcriptional and proteomic changes in apoptotic pathways and cell turnover underlie defective NK-cell homeostasis. [Display omitted]