Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation
Céline Posseme, Alba Llibre, Bruno Charbit, Vincent Bondet, Vincent Rouilly, Violaine Saint‐André, Jérémy Boussier, Jacob Bergstedt, Nikaïa Smith, Liam Townsend, Jamie Sugrue, Clíona Ní Cheallaigh, Niall Conlon, Maxime Rotival, Michael S. Kobor, Estelle Mottez, Stanislas Pol, Étienne Patin, Matthew L. Albert, Lluís Quintana‐Murci, Darragh Duffy, Laurent Abel, Andrés Alcover, Hugues Aschard, Philippe Bousso, Nollaig M. Bourke, Petter Brodin, Pierre Bruhns, Nadine Cerf–Bensussan, Ana Cumano, Caroline Demangel, Christophe d’Enfert, Ludovic Deriano, Marie‐Agnès Dillies, James P. Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes, Gunilla Karlsson Hedestam, Serge Herçberg, Molly A. Ingersoll, Rose Anne Kenny, Olivier Lantz, Mickaël Ménager, Frédérique Michel, Hugo Mouquet, Cliona O’Farrelly, Étienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Frédéric Rieux‐Laucat, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie‐Noëlle Ungeheuer, Christophe Zimmer, Matthew L. Albert, Darragh Duffy, Lluís Quintana‐Murci
Abstract
The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.