CD4 + T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent
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Abstract
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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SciScore for 10.1101/2021.06.02.446831: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more …
SciScore for 10.1101/2021.06.02.446831: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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