Maturation signatures of conventional dendritic cell subtypes in COVID‐19 suggest direct viral sensing

Growing evidence suggests that conventional dendritic cells (cDCs) undergo
aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of
effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients
suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope
with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we
report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the
upregulation of interferon-stimulated genes and interleukin (IL)-6 signaling pathways.
Furthermore, comparison of cDCs between patients with severe and mild disease showed
severely ill patients to exhibit profound downregulation of genes encoding molecules involved
in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed
the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus,
as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen
presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and
accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the
activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation.