Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation in health and disease

Celine Posseme (1, 2) , Alba Llibre (1) , Bruno Charbit (3) , Vincent Bondet (1) , Vincent Rouilly (4) , Violaine Saint-André (1, 5) , Jeremy Boussier (1) , Jacob Bergstedt (6) , Nikaïa Smith (1) , Maxime Rotival (6) , Michael S Kobor (7) , Tom Scriba (8) , Estelle Mottez (3) , Stanislas Pol (9) , Etienne Patin (6) , Matthew L. Albert (10) , Lluis Quintana-Murci (6, 11) , Darragh Duffy (1, 3) , Consortium Milieu Intérieur

1 Immunologie Translationnelle - Translational Immunology lab
2 ED 474 FIRE - Ecole Doctorale Frontiere de l’Innovation en Recherche et Education
3 UTechS CB - Cytometrie et Biomarqueurs – Cytometry and Biomarkers
4 Datactix
5 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
6 Génétique Evolutive Humaine - Human Evolutionary Genetics
7 University of British Columbia [Vancouver]
8 University of Cape Town
9 Département d'hépatologie [CHU Cochin]
10 Insitro [San Francisco]
11 CdF (institution) - Collège de France

The IL-12 family of cytokines comprises the only heterodimeric cytokines mediating diverse functional effects. We previously observed a bi-modal IL-12p70 response to LPS in healthy donors of the Milieu Interieur cohort. Herein, we demonstrate that IFNβ expression serves as an upstream determinant of variable IL-12p70 production. Integrative modelling of proteomic, genetic, epigenomic and cellular data confirmed IFNβ as key for regulation of LPS induced IL12A and IL-12p70 variability. The clinical relevance was supported by reduced and variable IL-12p70 responses in individuals infected with the hepatitis C virus (HCV), and findings that IFN-based therapy for HCV is more likely to fail in those patients with dysregulated pre-treatment IL-12p70 responses. In sum, our systems immunology approach has defined 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 in health and disease.

Mots clés: Cytokines; IL-12p70; IFNβ; systems immunology; immune variability; HCV

Domaines: Immunologie

Celine Posseme, Alba Llibre, Bruno Charbit, Vincent Bondet, Vincent Rouilly, et al.. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation in health and disease. 2021. ⟨pasteur-03244390v1⟩