{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T04:04:36Z","timestamp":1793505876263,"version":"4.5.0"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T00:00:00Z","timestamp":1771632000000},"content-version":"vor","delay-in-days":1361,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"The David Scaife Foundation","id":[{"id":"https:\/\/ror.org\/01my2h087","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 HL133184 (JM)"],"award-info":[{"award-number":["R01 HL133184 (JM)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000945","name":"The Pittsburgh Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000945","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The David Scaife Foundation","id":[{"id":"https:\/\/ror.org\/01my2h087","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH","award":["R01 HL133184 (JM)"],"award-info":[{"award-number":["R01 HL133184 (JM)"]}]},{"DOI":"10.13039\/100000945","name":"The Pittsburgh Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000945","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+\/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P\u2009&amp;lt;\u20090.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-\u03b1 (tumor necrosis factor-\u03b1) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-\u03b1+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n\u2009=\u200976; R\u2009=\u2009\u22120.797; P\u2009&amp;lt;\u20090.0001). In vitro TNF-\u03b1 blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P\u2009&amp;lt;\u20090.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NF\u03baB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-\u03b1 compared with peripheral blood mononuclear cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-\u03b1\/TNF receptor 1\u2013dependent through immune mechanisms that may contribute to lymphopenia. TNF-\u03b1 blockade may be beneficial in severe COVID-19.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202111-2493oc","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T11:45:06Z","timestamp":1648554306000},"page":"1403-1418","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":45,"title":["CD4+ T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-\u03b1\/Tumor Necrosis Factor Receptor 1\u2013Dependent"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-1223","authenticated-orcid":false,"given":"Iulia","family":"Popescu","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0092-9296","authenticated-orcid":false,"given":"Mark 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