CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent
Popescu, I.; Snyder, M. E.; Iasella, C. J.; Hannan, S. J.; Koshy, R.; Burke, R.; Das, A.; Brown, M. J.; Lyons, E. J.; Lieber, S. C.; Chen, X.; Sembrat, J. C.; An, X.; Linstrum, K.; Kitsios, G.; Konstantinidis, I.; Saul, M.; Kass, D. J.; Alder, J. K.; Chen, B. B.; Lendermon, E. A.; Kilaru, S.; Johnson, B.; Morrell, M. R.; Pilewski, J. M.; Kiss, J. E.; Wells, A. H.; Morris, A.; McVerry, B. J.; McMahon, D. K.; Triulzi, D. J.; Chen, K.; Sanchez, P. G.; McDyer, J. F.
Show 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-, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF- 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 NF{kappa}B signaling in S1-stimulated CD4+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF- versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-/TNFRI-dependent and therapies targeting TNF- may be beneficial in severe COVID-19. One Sentence SummaryAutocrine TNF-/TNFRI regulates CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease.
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