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

DUHALDE VEGA, MAITE; OLIVERA, DANIELA; GASTÃO DAVANZO, GUSTAVO; BERTULLO, MAURICIO; NOYA, VERÓNICA; FABIANO DE SOUZA, GABRIELA; PRIMON MURARO, STÉFANIE; CASTRO, ICARO; ARÉVALO, ANA PAULA; CRISPO, MARTINA; GALLIUSSI, GERMÁN; RUSSO, SOFÍA; CHARBONNIER, DAVID; RAMMAURO, FLORENCIA; JELDRES, MATHÍAS; ALAMÓN, CATALINA; VARELA, VALENTINA; BATTHYANY, CARLOS; BOLLATI-FOGOLÍN, MARIELA; OPPEZZO, PABLO; PRITSCH, OTTO; PROENÇA-MÓDENA, JOSÉ LUIZ; NAKAYA, HELDER I.; TRIAS, EMILIANO; BARBEITO, LUIS; ANEGON, IGNACIO; CUTURI, MARÍA CRISTINA; MORAES-VIEIRA, PEDRO; SEGOVIA, MERCEDES; HILL, MARCELO

Science Advances

Science Advances is the American Association for the Advancement of Science

Año: 2022 vol. 8

2375-2548

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 β-coronavirus. Tmem176b−/− mice infected with murine β-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 β-coronavirus disease.