Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation

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 (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 Centre for Molecular Medicine and Therapeutics
8 University of Cape Town
9 Département d'hépatologie [CHU Cochin]
10 Insitro [San Francisco]
11 Collège de France - Chaire Génomique humaine et évolution

The interleukine-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bi-modal IL-12p70 response to LPS stimulation in healthy donors. Herein, we demonstrate that IFNβ isa major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulatingmonocytes. Integrative modelling of proteomic, genetic, epigenomic and cellular data confirmsIFNβ as key forLPS induced IL-12p70, and allowed us to compare the relative effects of each of these parameters on variable cytokine responses.Clinical relevance of ourfindings is supportedby reduced IFNβ-IL-12p70 responses in patients hospitalized with acute SARS-CoV-2infection,or chronically infected with hepatitis C (HCV).Importantly these responses are resolved after viral clearance. Our systems immunology approach definesa better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into howcommon genetic and epigenetic variation may impact immune responses to bacterial infection.

Domains: Life Sciences [q-bio]; Immunology

Celine Posseme, Alba Llibre, Bruno Charbit, Vincent Bondet, Vincent Rouilly, et al.. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation. Cell Reports, 2022, ⟨10.1016/j.celrep.2022.110989⟩. ⟨pasteur-03244390⟩