PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical beta-coronavirus disease

Severe COVID-19 is associated with hyperinflammation and weak T cell responses against SARS-CoV-2. However, the links between those processes remain partially characterized. Moreover, whether and how therapeutically manipulating T cells may benefit patients are unknown. Our genetic and pharmacological evidence demonstrates that the ion channel TMEM176B inhibited inflammasome activation triggered by SARS-CoV-2 and SARS-CoV-2-related murine beta-coronavirus. Tmem176b(-/-) mice infected with murine beta-coronavirus developed inflammasome-dependent T cell dysfunction and critical disease, which was controlled by modulating dysfunctional T cells with PD-1 blockers. In critical COVID-19, inflammasome activation correlated with dysfunctional T cells and low monocytic TMEM176B expression, whereas PD-L1 blockade rescued T cell functionality. Here, we mechanistically link T cell dysfunction and inflammation, supporting a cancer immunotherapy to reinforce T cell immunity in critical beta-coronavirus disease.

Automated summary

This study reveals the correlation between inflammation and dysfunctional T cell responses, showing that manipulating T cells can control certain viral infections. These findings provide new insights for supporting immunotherapy targeting critical viral diseases.