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

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Vega, Maite Duhalde ; Olivera, Daniela ; Davanzo, Gustavo Gastao ; Bertullo, Mauricio ; Noya, Veronica ; de Souza, Gabriela Fabiano ; Muraro, Stefanie Primon ; Castro, Icaro ; Arevalo, Ana Paula ; Crispo, Martina ; Galliussi, German ; Russo, Sofia ; Charbonnier, David ; Rammauro, Florencia ; Jeldres, Mathias ; Alamon, Catalina ; Varela, Valentina ; Batthyany, Carlos ; Bollati-Fogolin, Mariela ; Oppezzo, Pablo ; Pritsch, Otto ; Proenca-Modena, Jose Luiz ; Nakaya, Helder I. ; Trias, Emiliano ; Barbeito, Luis ; Anegon, Ignacio ; Cuturi, Maria Cristina ; Moraes-Vieira, Pedro ; Segovia, Mercedes ; Hill, Marcelo

• Document type: Journal article
• Source: SCIENCE ADVANCES; v. 8, n. 38, p. 13-pg., 2022-09-23.

Abstract

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. (AU)

• FAPESP's process: 20/04558-0 - Characterization of intrinsic risk factors and the development of new diagnostic and treatment alternatives for COVID-19
• Grantee: José Luiz Proença Módena
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/04579-7 - Study of the risk factors associated with greater severity to COVID-19 and mapping of the metabolic pathways required for the anti-SARS-CoV-2 response
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Regular Research Grants