{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T07:19:54Z","timestamp":1778915994350,"version":"3.51.4"},"reference-count":56,"publisher":"American Society of Hematology","issue":"5","license":[{"start":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T00:00:00Z","timestamp":1635206400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1182\/blood.2021013233","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T19:05:12Z","timestamp":1635275112000},"page":"704-716","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia"],"prefix":"10.1182","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1942-0040","authenticated-orcid":false,"given":"Ebba","family":"Sohlberg","sequence":"first","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, 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and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8197-308X","authenticated-orcid":false,"given":"Anette","family":"M\u00f6rtberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden;"},{"name":"Medical Unit Clinical Immunology and Transfusion Medicine and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petter","family":"H\u00f6glund","sequence":"additional","affiliation":[{"name":"Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, and"},{"name":"Medical Unit Clinical Immunology and Transfusion Medicine and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9871-0961","authenticated-orcid":false,"given":"Mikael","family":"Sundin","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden;"},{"name":"Section of Pediatric Hematology\/Immunology\/Hematopoietic Cell Transplantation, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00f6ran","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Section of Pediatric Hematology\/Immunology\/Hematopoietic Cell Transplantation, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Palmblad","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, Stockholm, Sweden; and"},{"name":"The Hematology Center, Karolinska University Hospital Huddinge, Stockholm, 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