Tu168 - Age-Related Patterns of Type II Interferon Immunity: Implications for Intramacrophagic Infections and MSMD Diagnosis During Childhood

Abstract Text: Type II interferon (IFN) immunity is crucial for controlling intramacrophagic infections, driven by the interaction between innate immunity (macrophage-derived IL-12) and adaptive immunity (Th-derived IFN-γ). This study examines the maturation of type II IFN immunity in 55 healthy children (ages 1–18) to enable proper identification of deficiencies as part of the diagnostic evaluation of Mendelian Susceptibility to Mycobacterial Diseases (MSMD). The IL-12/IFN-γ axis was assessed through: 1) cytokine production after mycobacterial stimulation (Luminex and ELISA for IFN-γ, IL-12p70, TNF, IP-10, IL-1RA, IL-10, IL-1β and IL-6), 2) IFN-γR1/R2 expression on monocytes, and 3) STAT1 phosphorylation/dephosphorylation. T cell maturation, as the primary IFN-γ source, was evaluated via extended immunophenotyping (naïve/memory/activated, Th1; Th2; Th17; Th1/17; Tfh) and proliferation assays.

Main findings: 1) stable expression/production of key components of the IL-12/IFN-γ axis (IFN-γ, IL-12, TNF, IFN-γR1/2, and STAT1 activity) across ages confirming the stability of innate immune function throughout childhood; 2) increasing responses to IFN-γ with age reflected by increased IP-10 production, and increased in the IFN-γ counter-acting anti-inflammatory cytokines (IL-10, IL-1RA); and 3) progressive T cell maturation, including Th1, Th17 and Th1/17 subsets, with significant milestones between 6–8.6 years, while T cell proliferative capacity remained stable.

These observations highlight the stability of IL-12/IFN-γ axis innate components with age, accompanied by enhanced downstream IFN-γ signaling, aligning with the maturation of Th cell compartment. These underscored the limited need for age-specific evaluation of IL-12/IFN-γ axis innate components in MSMD diagnosis, while emphasizing the importance of T cell profiling due to its progressive maturation.