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