TY - JOUR T1 - CD4+ T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1-Dependent. AU - Popescu,Iulia, AU - Snyder,Mark E, AU - Iasella,Carlo J, AU - Hannan,Stefanie J, AU - Koshy,Ritchie, AU - Burke,Robin, AU - Das,Antu, AU - Brown,Mark J, AU - Lyons,Emily J, AU - Lieber,Sophia C, AU - Chen,Xiaoping, AU - Sembrat,John C, AU - Bhatt,Payal, AU - Deng,Evan, AU - An,Xiaojing, AU - Linstrum,Kelsey, AU - Kitsios,Georgios, AU - Konstantinidis,Ioannis, AU - Saul,Melissa, AU - Kass,Daniel J, AU - Alder,Jonathan K, AU - Chen,Bill B, AU - Lendermon,Elizabeth A, AU - Kilaru,Silpa, AU - Johnson,Bruce, AU - Pilewski,Joseph M, AU - Kiss,Joseph E, AU - Wells,Alan H, AU - Morris,Alison, AU - McVerry,Bryan J, AU - McMahon,Deborah K, AU - Triulzi,Darrell J, AU - Chen,Kong, AU - Sanchez,Pablo G, AU - McDyer,John F, PY - 2022/3/30/pubmed PY - 2022/6/18/medline PY - 2022/3/29/entrez KW - CD4+ T cells KW - COVID-19 KW - SARS-CoV-2 infection KW - TNF-α KW - lymphopenia SP - 1403 EP - 1418 JF - American journal of respiratory and critical care medicine JO - Am J Respir Crit Care Med VL - 205 IS - 12 N2 - Rationale: 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. Objectives: 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. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: 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 < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α 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 < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB 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-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19. SN - 1535-4970 UR - https://www.unboundmedicine.com/medline/citation/35348444/CD4+_T_Cell_Dysfunction_in_Severe_COVID_19_Disease_Is_Tumor_Necrosis_Factor_α/Tumor_Necrosis_Factor_Receptor_1_Dependent_ DB - PRIME DP - Unbound Medicine ER -