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Here, we studied their impact on type 2 lymphocytes in severe asthma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed high\u2010parameter flow cytometry analysis of peripheral blood mononuclear cells from 40 patients with severe asthma before, and after 4 and 12\u2009months of mepolizumab (<jats:italic>n<\/jats:italic>\u2009=\u200933) or dupilumab (<jats:italic>n<\/jats:italic>\u2009=\u20097) treatment, focusing on type 2 lymphocytes. Additionally, we performed single\u2010cell RNA sequencing (scRNA\u2010seq) (<jats:italic>n<\/jats:italic> = 3) and stimulation experiments of type 2 lymphocytes (<jats:italic>n<\/jats:italic>\u2009=\u20093) to explore transcriptional and functional changes associated with mepolizumab treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mepolizumab treatment increased circulating type 2 innate lymphoid cell (ILC2), type 2\u2009T helper (Th2) and type 2 cytotoxic (Tc2) cell frequencies, skewing ILC2 towards a CD117<jats:sup>low<\/jats:sup> signature with high CD62L expression, and Th2\/Tc2 cells towards a CD45RA<jats:sup>\u2212<\/jats:sup>CD62L<jats:sup>+<\/jats:sup> central memory phenotype. Dupilumab\u2010treated patients also showed increased frequencies of total ILC2 and CD117<jats:sup>low<\/jats:sup> ILC2. Mepolizumab treatment reduced the expression of tissue homing receptors <jats:italic>CXCR4<\/jats:italic> in ILC2, and <jats:italic>GPR183<\/jats:italic> in ILC2, Th2, and Tc2 cells while enhancing their type 2 cytokine producing capability in response to alarmins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Mepolizumab increases the frequencies of circulating ILC2, Th2, and Tc2 cells, with reduced tissue homing receptor expression but increased type 2 cytokine production potential. This reveals a potentially new mechanism for how mepolizumab reduces airway inflammation by re\u2010directing trafficking of inflammatory type 2 lymphocytes away from airway\u2010homing, with implications for the possibility of achieving biologics\u2010free remission in asthma.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.16633","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T03:04:26Z","timestamp":1750907066000},"page":"2541-2556","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["High\u2010Dimensional Analysis of Type 2 Lymphocyte Dynamics During Mepolizumab or Dupilumab Treatment in Severe Asthma"],"prefix":"10.1111","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4795-7814","authenticated-orcid":false,"given":"Lorenz","family":"Wirth","sequence":"first","affiliation":[{"name":"Department of Medicine Huddinge, Center for Infectious Medicine Karolinska 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