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

Abstract

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.

Discovering hub genes involved in the pathophysiological impact of COVID-19 on diabetes kidney disease by differential gene expression and interactome analysis

“…patients. These increased levels are associated with disease severity [96,97]. These results corroborate the important role of immune cell activation persistent in chronic kidney disease combined with the expression ISG15, STAT1 and MX1 could contribute to higher expression of proinflammatory cytokines potency and participate in the complication by SARS-CoV-2 infection.…”

T cell dysregulation in inflammatory diseases in ICU

“…These TNFα + CD4 + cells have reduced proliferation and increased susceptibility to AICD. Treatment with infliximab or anti-TNF receptor 1 antibody was able to reverse AICD and increase CD4 + cells proliferation [ 41 ]. T-cell autophagy deficiency Autophagy is another type of programmed cell death that is essential for cellular homeostasis.…”

“…These TNFα + CD4 + cells have reduced proliferation and increased susceptibility to AICD. Treatment with infliximab or anti-TNF receptor 1 antibody was able to reverse AICD and increase CD4 + cells proliferation [ 41 ].…”

Systems Anesthesiology: Integrating Insights From Diverse Disciplines to Improve Perioperative Care

“…Defects in T-cell immunity are a common feature in patients with severe coronavirus disease 2019 (COVID-19). 13 The analysis of plasma protein biomarkers from patients with ARDS identified "hyperinflammatory" and "hypoinflammatory" subphenotypes with distinct outcomes (higher mortality in the hyperinflammatory phenotype), and distinct responses to PEEP and fluid therapy. 6 These findings increased our understanding of ARDS pathogenesis and heterogeneity; however, there has been a lack of therapeutic translation thus far.…”