The UPR sensor IRE1α promotes dendritic cell responses to control Toxoplasma gondii infection

Anaïs F Poncet (1) , Victor Bosteels (2, 3) , Eik Hoffmann (1) , Sylia Chehade (1) , Sofie Rennen (2, 3) , Ludovic Huot (1) , Véronique Peucelle (1) , Sandra Maréchal (2, 3) , Jamal Khalife (1) , Nicolas Blanchard (4) , Sophie Janssens (2, 3) , Sabrina Marion (1)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 VIB - Vlaams Instituut voor Biotechnologie [Ghent, Belgique]
3 UGENT - Universiteit Gent = Ghent University
4 CPTP - Centre de Physiopathologie Toulouse Purpan

The unfolded protein response (UPR) has emerged as a central regulator of immune cell responses in several pathologic contexts including infections. However, how intracellular residing pathogens modulate the UPR in dendritic cells (DCs) and thereby affect T cell-mediated immunity remains uncharacterized. Here, we demonstrate that infection of DCs with Toxoplasma gondii (T. gondii) triggers a unique UPR signature hallmarked by the MyD88-dependent activation of the IRE1α pathway and the inhibition of the ATF6 pathway. Induction of XBP1s controls pro-inflammatory cytokine secretion in infected DCs, while IRE1α promotes MHCI antigen presentation of secreted parasite antigens. In mice, infection leads to a specific activation of the IRE1α pathway, which is restricted to the cDC1 subset. Mice deficient for IRE1α and XBP1 in DCs display a severe susceptibility to T. gondii and succumb during the acute phase of the infection. This early mortality is correlated with increased parasite burden and a defect in splenic T-cell responses. Thus, we identify the IRE1α/XBP1s branch of the UPR as a key regulator of host defense upon T. gondii infection.

Mots clés: antigen presentation; cytokines; dendritic cells; Toxoplasma gondii; UPR

Domaines: Microbiologie et Parasitologie

Anaïs F Poncet, Victor Bosteels, Eik Hoffmann, Sylia Chehade, Sofie Rennen, et al.. The UPR sensor IRE1α promotes dendritic cell responses to control Toxoplasma gondii infection. EMBO Reports, 2021, 22 (3), pp.e49617. ⟨10.15252/embr.201949617⟩. ⟨hal-03286981⟩