{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T02:13:32Z","timestamp":1773195212870,"version":"3.50.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>COVID-19 vaccination has significantly reduced mortality and morbidity. Recent studies in unvaccinated people indicate a more complex immune response beyond just the cytokine storm. Understanding changes in the immune cell network is crucial for identifying vaccine-independent immune imbalances, especially in vaccine-na\u00efve patients needing invasive mechanical ventilation (IMV). This knowledge could help improve vaccine development and find biomarkers linked to severe COVID-19.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Peripheral blood immune cells from vaccine-na\u00efve COVID-19 patients from the first pandemic wave were classified into those who required IMV and those who did not (No-IMV). High-dimensional immune phenotyping was performed using multiparametric flow cytometry combined with FlowSOM clustering and UMAP for dimensionality reduction. Additionally, T-cell activation efficiency after polyclonal stimulation was evaluated\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IMV patients, but not No-IMV, exhibited a marked disruption of immune cell networks, characterized by a loss of immune checkpoint (IC)-expressing T-cell subsets, particularly PD-1- and LAG-3-expressing T cells. Conversely, there was an increase in the frequency of T cells co-expressing molecules linked to inflammatory pathways (TNF\/TNFR) and cell death (CD95L). These changes were also associated with reduced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell activation capacity and the rise of non-conventional cytotoxic CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell subsets. In the B-cell compartment, IMV patients displayed depletion of CCR7+ subsets and decreased PD-1 expression. Additionally, higher frequencies of NK and NKT cells expressing TNF pathway-related molecules were observed. While classical monocyte subsets expressing ICs such as PD-L1, PD-L2, and TIM-3 remained stable, non-classical monocyte subsets showed altered IC expression. In contrast, No-IMV patients maintained a relatively balanced immune architecture.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Vaccine-na\u00efve COVID-19 patients requiring IMV display an immune landscape distinct from that of No-IMV patients. IMV exhibits a profound imbalance in innate and adaptive immune cell networks, characterized by inflammatory skewing, loss of regulatory subsets, and impaired cytotoxic T-cell functionality, features not observed in No-IMV. These findings reveal coordinated immune alterations beyond cytokine hyperinflammation and identify cellular immune signatures associated with severe COVID-19.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1794103","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T05:31:41Z","timestamp":1773120701000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Imbalanced immune cell network and suboptimal cell activation: signatures associated with disease severity in vaccine-na\u00efve COVID-19 patients"],"prefix":"10.3389","volume":"17","author":[{"given":"Ranferi","family":"Oca\u00f1a-Guzman","sequence":"first","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Integrativa, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas","place":["Mexico City, 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