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However, whether ADCC is a pathogenic mechanism in patients with these conditions has not been confirmed. We sought to characterize circulatory NK cells using functional assays, phenotyping, and transcriptomics to elucidate their role in pathology. NK cells from NMOSD patients and MG patients with elevated disease burden exhibited reduced ADCC and CD56dimCD16hi NK cells, along with an elevated frequency of CD56dimCD16dim\/\u2212 NK cells. We determined that ADCC induces a similar phenotypic shift in vitro. Bulk RNA sequencing distinguished the CD56dimCD16dim\/\u2212 population from the canonical CD56dimCD16hi cytotoxic and CD56hiCD16\u2212 immunomodulatory subsets, as well as CD56hiCD16+ NK cells. Multiparameter immunophenotyping of NK cell markers, functional proteins, and receptors similarly showed that the CD56dimCD16dim\/\u2212 subset exhibits a unique profile while still maintaining expression of characteristic NK markers CD56, CD94, and NKp44. Notably, expression of perforin and granzyme is reduced in comparison with CD56dimCD16hi NK cells. Moreover, they exhibit elevated trogocytosis capability, HLA-DR expression, and many chemokine receptors, including CCR7. In contrast with NMOSD and MG, myelin oligodendrocyte glycoprotein Ab disease NK cells did not exhibit functional, phenotypic, or transcriptomic perturbations. In summary, CD56dimCD16dim\/\u2212 NK cells are a distinct peripheral blood immune cell population in humans elevated upon prior cytotoxic activity by the CD56dimCD16hi NK cell subset. The elevation of this subset in NMOSD and MG patients suggests prior ADCC activity.<\/jats:p>","DOI":"10.4049\/jimmunol.2300015","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T13:53:27Z","timestamp":1705931607000},"page":"785-800","source":"Crossref","is-referenced-by-count":10,"title":["A Noncanonical CD56dimCD16dim\/\u2212 NK Cell Subset Indicative of Prior Cytotoxic Activity Is Elevated in Patients with Autoantibody-Mediated Neurologic Diseases"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0325-6488","authenticated-orcid":false,"given":"Soumya S","family":"Yandamuri","sequence":"first","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT"},{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4166-5650","authenticated-orcid":false,"given":"Beata","family":"Filipek","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT"},{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT"},{"name":"Department of Pharmaceutical Microbiology and Biochemistry, Medical University of Lodz , Lodz ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7367-1364","authenticated-orcid":false,"given":"Nikhil","family":"Lele","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5807-2635","authenticated-orcid":false,"given":"Inessa","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3346-1394","authenticated-orcid":false,"given":"Jeffrey L","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Neurology, Programs in Neuroscience and Immunology, University of Colorado School of Medicine , Anschutz Medical Campus, Aurora, CO"},{"name":"Department of Ophthalmology, Programs in Neuroscience and Immunology, University of Colorado School of Medicine , Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8812-1637","authenticated-orcid":false,"given":"Elias S","family":"Sotirchos","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University , Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1179-3937","authenticated-orcid":false,"given":"Erin E","family":"Longbrake","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-7393","authenticated-orcid":false,"given":"Emily M","family":"Mace","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7056-419X","authenticated-orcid":false,"given":"Kevin C","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT"},{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,22]]},"reference":[{"key":"2025020405460145200_r1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1084\/jem.20050304","article-title":"IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel","volume":"202","author":"Lennon","year":"2005","journal-title":"J. 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