Author: Popescu, Iulia; Snyder, Mark E.; Iasella, Carlo J.; Hannan, Stefanie J.; Koshy, Ritchie; Burke, Robin; Das, Antu; Brown, Mark J.; Lyons, Emily J.; Lieber, Sophia C.; Chen, Xiaoping; Sembrat, John C.; An, Xiaojing; Linstrum, Kelsey; Kitsios, Georgios; Konstantinidis, Ioannis; Saul, Melissa; Kass, Daniel J.; Alder, Jonathan K.; Chen, Bill B.; Lendermon, Elizabeth A.; Kilaru, Silpa; Johnson, Bruce; Morrell, Matthew R.; Pilewski, Joseph M.; Kiss, Joseph E.; Wells, Alan H.; Morris, Alison; McVerry, Bryan J.; McMahon, Deborah K.; Triulzi, Darrell J.; Chen, Kong; Sanchez, Pablo G.; McDyer, John F.
Title: CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent Cord-id: yft33obm Document date: 2021_6_3
ID: yft33obm
Snippet: Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. 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 to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced ce
Document: Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. 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 to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF-α blockade including infliximab or anti-TNFRI antibodies strikingly rescued S1-specific CD4+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P<0.001). Single-cell RNAseq demonstrated downregulation of Type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19. One Sentence Summary Autocrine TNF-α/TNFRI regulates CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease.
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