Early IFNβ Secretion Determines Variable Downstream IL-12p70 Responses Upon TLR4 Activation

The IL-12 family of cytokines 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 expression serves as the major 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 IL-12A and IL-12p70 variability, and allowed us to quantify the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings was supported by reduced TLR4 induced IFNβ-IL-12p70 responses in patients hospitalized with acute SARS-CoV-2 infection, or chronically infected with hepatitis C (HCV). Furthermore, HCV patients that failed IFN-based therapy had 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.