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) , Liam Townsend (7, 8) , James A. Sugrue (8) , Clíona Ní Cheallaigh (7, 8) , Niall Conlon (7, 8) , Maxime Rotival (6) , Michael S Kobor (9) , Estelle Mottez (3) , Stanislas Pol (10) , Etienne Patin (6) , Matthew L. Albert (11) , Lluis Quintana-Murci (6, 12) , 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 St James’s Hospital [Dublin, Ireland]
8 Trinity College Dublin
9 University of British Columbia [Vancouver]
10 Hôpital Cochin [AP-HP]
11 HIBIO [South San Francisco]
12 Collège de France - Chaire Génomique humaine et évolution

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.

Mots clés: Cytokine variability; TLR4 immune responses; IL-12p70; type I interferons; systems immunology

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. Cell Reports, 2022, 39 (13), pp.110989. ⟨10.1016/j.celrep.2022.110989⟩. ⟨pasteur-03244390v2⟩