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

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Posseme, Celine | Llibre, Alba | Charbit, Bruno | Bondet, Vincent | Rouilly, Vincent | Saint-André, Violaine | Boussier, Jeremy | Bergstedt, Jacob | Smith, Nikaïa | Townsend, Liam | Sugrue, James, A. | Cheallaigh, Clíona Ní | Conlon, Niall | Rotival, Maxime | Kobor, Michael, S | Mottez, Estelle | Pol, Stanislas | Patin, Etienne | Albert, Matthew, L. | Quintana-Murci, Lluis | Duffy, Darragh | Milieu Intérieur, Consortium

Edité par CCSD ; Elsevier Inc -

International audience. 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.

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