CD4 + T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1-Dependent.

Autor: Popescu I; Division of Pulmonary, Allergy, and Critical Care Medicine., Snyder ME; Division of Pulmonary, Allergy, and Critical Care Medicine., Iasella CJ; Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania., Hannan SJ; Division of Pulmonary, Allergy, and Critical Care Medicine., Koshy R; Division of Pulmonary, Allergy, and Critical Care Medicine., Burke R; Division of Pulmonary, Allergy, and Critical Care Medicine., Das A; Division of Pulmonary, Allergy, and Critical Care Medicine., Brown MJ; Division of Pulmonary, Allergy, and Critical Care Medicine., Lyons EJ; Division of Pulmonary, Allergy, and Critical Care Medicine., Lieber SC; Division of Pulmonary, Allergy, and Critical Care Medicine., Chen X; Division of Pulmonary, Allergy, and Critical Care Medicine., Sembrat JC; Division of Pulmonary, Allergy, and Critical Care Medicine., Bhatt P; Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania., Deng E; Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania., An X; Division of Pulmonary, Allergy, and Critical Care Medicine., Linstrum K; Department of Critical Care Medicine., Kitsios G; Division of Pulmonary, Allergy, and Critical Care Medicine., Konstantinidis I; Division of Pulmonary, Allergy, and Critical Care Medicine., Saul M; Department of Medicine., Kass DJ; Division of Pulmonary, Allergy, and Critical Care Medicine., Alder JK; Division of Pulmonary, Allergy, and Critical Care Medicine., Chen BB; Division of Pulmonary, Allergy, and Critical Care Medicine.; Aging Institute., Lendermon EA; Division of Pulmonary, Allergy, and Critical Care Medicine., Kilaru S; Division of Pulmonary, Allergy, and Critical Care Medicine., Johnson B; Division of Pulmonary, Allergy, and Critical Care Medicine., Pilewski JM; Division of Pulmonary, Allergy, and Critical Care Medicine., Kiss JE; Division of Transfusion Medicine., Wells AH; Division of Laboratory Medicine, Department of Pathology., Morris A; Division of Pulmonary, Allergy, and Critical Care Medicine., McVerry BJ; Division of Pulmonary, Allergy, and Critical Care Medicine., McMahon DK; Division of Infectious Diseases, and., Triulzi DJ; Division of Transfusion Medicine., Chen K; Division of Pulmonary, Allergy, and Critical Care Medicine., Sanchez PG; Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and., McDyer JF; Division of Pulmonary, Allergy, and Critical Care Medicine.
Jazyk: angličtina
Zdroj: American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2022 Jun 15; Vol. 205 (12), pp. 1403-1418.
DOI: 10.1164/rccm.202111-2493OC
Abstrakt: 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.
Databáze: MEDLINE
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