| Autor: |
Iulia Popescu, Mark E. Snyder, Carlo J. Iasella, Stefanie J. Hannan, Ritchie Koshy, Robin Burke, Antu Das, Mark J. Brown, Emily J. Lyons, Sophia C. Lieber, Xiaoping Chen, John C. Sembrat, Payal Bhatt, Evan Deng, Xiaojing An, Kelsey Linstrum, Georgios Kitsios, Ioannis Konstantinidis, Melissa Saul, Daniel J. Kass, Jonathan K. Alder, Bill B. Chen, Elizabeth A. Lendermon, Silpa Kilaru, Bruce Johnson, Joseph M. Pilewski, Joseph E. Kiss, Alan H. Wells, Alison Morris, Bryan J. McVerry, Deborah K. McMahon, Darrell J. Triulzi, Kong Chen, Pablo G. Sanchez, John F. McDyer |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
American journal of respiratory and critical care medicine, 205(12):1403-1418 |
| Popis: |
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-alpha (tumor necrosis factor-alpha) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4(+) TNF-alpha(+) 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-alpha 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 NFKB 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-alpha compared with peripheral blood mononuclear cells. CONCLUSIONS: Together, our findings show CD4(+) dysfunction in severe COVID-19 is TNF-alpha/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-alpha blockade may be beneficial in severe COVID-19. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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