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

[tetano]

Sci Adv


. 2022 Sep 23;8(38):eabn6545.
doi: 10.1126/sciadv.abn6545. Epub 2022 Sep 21.
PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical β-coronavirus disease


Maite Duhalde Vega ¹ , Daniela Olivera ^{1 2} , Gustavo Gastão Davanzo ³ , Mauricio Bertullo ⁴ , Verónica Noya ⁵ , Gabriela Fabiano de Souza ⁶ , Stéfanie Primon Muraro ⁶ , Icaro Castro ⁷ , Ana Paula Arévalo ⁸ , Martina Crispo ⁸ , Germán Galliussi ⁹ , Sofía Russo ^{1 2} , David Charbonnier ¹ , Florencia Rammauro ^{2 10} , Mathías Jeldres ^{1 2} , Catalina Alamón ¹¹ , Valentina Varela ¹¹ , Carlos Batthyany ⁹ , Mariela Bollati-Fogolín ¹² , Pablo Oppezzo ¹³ , Otto Pritsch ^{2 10} , José Luiz Proença-Módena ⁶ , Helder I Nakaya ⁷ , Emiliano Trias ¹¹ , Luis Barbeito ¹¹ , Ignacio Anegon ¹⁴ , María Cristina Cuturi ¹⁴ , Pedro Moraes-Vieira ³ , Mercedes Segovia ^{1 2} , Marcelo Hill ^{1 2}



Affiliations

• PMID: 36129987
• DOI: 10.1126/sciadv.abn6545

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 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.